法尼基焦磷酸合成酶在心血管重塑中的作用研究
|
摘要
研究背景：
心肌肥厚和充血性心力衰竭是全世界人类死亡的主要原因之一。心肌肥厚是心力衰竭早期心肌细胞对室壁应力增加的一种重要的适应性、代偿性反应,最终会导致充血性心力衰竭。
法尼基焦磷酸合成酶(famesyl pyrophosphate synthase, FPPS)是甲羟戊酸途径中的一种关键酶,它催化合成异戊二烯化产物,包括法尼基焦磷酸(FPP)和牻牛儿牻牛儿焦磷酸(GGPP)。最新的研究表明FPPS在血管紧张素Ⅱ (Ang Ⅱ)诱导的心肌肥厚细胞中以及自发性高血压大鼠中表达明显增高,同时在自发性高血压大鼠中抑制FPPS可以减轻心肌肥厚和改善血管重塑。这些结果都与RhoA相关,而GGPP对RhoA的牻牛儿牻牛儿焦磷酸化和活化非常重要。
目的：
本研究利用转基因动物模型来进一步探讨FPPS与心肌肥厚和心力衰竭的关系,并研究其机制。
方法：
(1)构建心脏特异性过表达FPPS转基因模型。
(2)使用real-time PCR、western-blot、免疫组化等技术检测转基因小鼠心脏组织中FPPS表达水平。
(3)使用高效液相色谱法(HPLC)技术检测转基因小鼠心脏组织中FPP和GGPP水平,酶法测定组织胆固醇浓度。
(4)使用超声心动图、病理染色、心导管等方法检测转基因小鼠心脏功能及形态学变化。
(5)使用real-time PCR技术检测小鼠心脏心肌肥厚基因(ANP、BNP、β-MHC)以及心肌纤维化基因(TGF-β、CTGF)表达。
(6)使用G-Lisa方法检测小鼠心脏RhoA、Rac1、Cdc42、Ras等小G蛋白表达水平,使用western-blot方法检测小鼠心脏Erk1/2、P38MAPK、 Akt/GSK3β等的活性。
(7)表达FPPS的腺病毒感染心肌细胞,免疫荧光鉴定心肌细胞表面积。FPPS抑制剂阿伦磷酸钠或者Rho的抑制剂C3exoenzyme、Ras抑制剂farnesylthiosalicylic acid (FTS)在感染后加入心肌细胞。
(8)在腺病毒感染的心肌细胞中检测RhoA、Ras、Erk1/2、P38MAPK、 Akt/GSK3β等活性。
(9)使用HPLC技术检测心肌细胞中FPP和GGPP水平,酶法测定细胞胆固醇浓度。
结果：
(1)转基因小鼠心脏组织中FPPS表达明显增加。
(2)心脏特异性表达FPPS增加了FPP和GGPP、胆固醇合成。
(3)心脏特异性表达FPPS诱导心肌肥厚基因(ANP、BNP、β-MHC)、心肌纤维化基因(TGF-β、CTGF)表达增高,最终导致心肌肥厚、纤维化、心力衰竭。
(4)心肌细胞腺病毒过表达FPPS诱导心肌细胞肥厚基因表达、细胞体积增大。心肌细胞中加入阿伦磷酸钠或者C3exoenzyme可抑制FPPS过表达导致的心肌细胞肥大。
(5)心脏特异性表达FPPS诱导RhoA活性增高,磷酸化的ERK和p38表达上调,与体内结果一致,心肌细胞腺病毒过表达FPPS导致RhoA活性增高,磷酸化的ERK和p38表达上调。
结论：
FPPS及FPPS调控的信号转导通路在心肌重塑过程中具有重要的作用。
研究背景：
血管紧张素Ⅱ (AngⅡ)是一种血管加压素,肾素-血管紧张素系统(RAS)的八肽激素中间体。相当多的证据表明,AngⅡ在心肌肥厚和纤维化起着重要的作用。在以往的研究中,我们发现FPPS的表达水平在AngⅡ刺激的肥厚心肌细胞中显著增加,这表明FPPS在AngⅡ引起的心肌肥厚中发挥着重要的作用。另外也研究发现在心肌细胞中通过小分子RNA干扰抑制FPPS基因表达或者药物阿伦磷酸钠抑制FPPS可以阻止AngⅡ诱导的心肌细胞肥大。
目的：
本研究观察抑制FPPS对体内AngⅡ介导的心肌肥厚和纤维化的影响,并探讨其机制。
方法：
(1)野生型小鼠分为四组：生理盐水,血管紧张素Ⅱ(2.88毫克/公斤/天),阿伦磷酸钠(0.1毫克/公斤/天),或血管紧张素Ⅱ(2.88毫克/公斤/天)和阿伦磷酸钠(0.1毫克/公斤/天)持续微泵注射4周。
(2)使用real-time PCR、western-blot等技术检测各组小鼠心脏组织中FPPS表达水平。
(3)使用HPLC技术检测各组小鼠心脏组织中FPP和GGPP水平。
(4)使用超声心动图、病理染色等方法检测各组小鼠心脏功能及形态学变化。
(5)使用real-time PCR技术检测各组小鼠心肌肥厚基因(ANP、BNP)以及心肌纤维化基因(TGF-β1、Procollagen Ⅰ、Procollagen Ⅲ)表达。
(6)使用G-Lisa方法检测RhoA蛋白表达水平, western-blot方法检测P38MAPK的活性。
结果：
(1) AngⅡ诱导小鼠心肌肥厚和纤维化。
(2)抑制FPPS改善AngⅡ诱导的小鼠心肌肥厚和纤维化。
(3) AngⅡ增加FPPS的表达,抑制FPPS减少AngⅡ小鼠中磷酸化P-38的表达。
(4)抑制FPPS降低AngⅡ诱导的ANP, BNP, TGF-β1, Procollagen Ⅰ, Procollagen ⅢmRNA及ANP, TGF-β1, collagen Ⅰ, collagen Ⅲ蛋白表达增加。
(5)抑制FPPS降低AngⅡ诱导的FPP和GGPP水平增加
(6)抑制FPPS减少AngⅡ诱导的RhoA活性增加。
结论：
FPPS在AngⅡ诱导的心肌肥厚和纤维化过程中具有重要的作用,至少部分是通过抑制RhoA的活化,减少p38的磷酸化和下调TGF-β1的表达来实现的。
Background:
Cardiac hypertrophy and heart failure are leading causes of morbidity and mortality worldwide. Cardiac hypertrophy is thought to be an adaptive response to pressure and/or volume overload, which enables the heart to normalize ventricular-wall tension and improve pump function. However, a sustained or excessive hypertrophic response is considered to be maladaptive on the basis of the progression towards heart failure. Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. FPPS catalyzes the synthesis of farnesyl pyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The latter is essential for geranylgeranylation and activation of RhoA. In our previous study we find that inhibition of FPPS attenuates cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and prevents angiotensin (Ang) Ⅱ-induced hypertrophy in cardiomyocytes.
Aims:
We further investigate the role of FPPS in cardiac hypertrophy and heart failure (HF) using transgenic (Tg) model, and its mechanisms.
Methods:
Tg mice with cardiac-specific expression of FPPS were studied as an experimental model.
(1) FPPS expression was measured in Tg mice by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry.
(2) FPP and GGPP levels in Tg mice were measured by HPLC as well as cholesterol concentrations were measured by enzymatic determination.
(3) Cardiac function and morphological changes of Tg mice were investigated by echocardiography, pathological analysis, and cardiac catheterization.
(4) ANP, BNP, β-MHC and TGF-β, CTGF mRNA expression in Tg mice were measured by qRT-PCR.
(5) RhoA, Rac1, Cdc42and Ras activation in Tg mice were measured by G-Lisa method. Besides, the activities of Erkl/2, P38mitogen-activated protein kinases (MAPK) and Akt/GSK3β were detected by western blot analysis.
(6) Areas of cultured neonatal cardiomyocytes infected by adenovirus were detected by immunofluorescence. Alendronate and C3exoenzyme, FTS were added after infection.
(7) RhoA and Ras activation in cardiomyocytes were measured by G-Lisa method. Besides, the activities of Erk1/2, P38MAPK and Akt/GSK3β were detected by western blot analysis.
(8) FPP and GGPP levels in cardiomyocytes were measured by HPLC as well as cholesterol concentration in cardiomyocytes was measured by enzymatic determination.
Results:
(1) FPPS expression was increased in Tg heart.
(2) FPP, GGPP and cholesterol levels were increased in Tg heart.
(3) Tg mice with overexpression of FPPS exhibited cardiac hypertrophy, fibrosis and heart failure as well as enhanced expression of ANP, BNP, β-MHC and TGF-β, CTGF.
(4) These pathological changes were associated with activation of RhoA and other known kinases in the hypertrophic signaling pathways, such as extracellular signal-related kinases1/2(ERK1/2) and p38.
(5) Adenoviral infection of FPPS in cultured neonatal cardiomyocytes induced a hypertrophic response characterized by increased cell size and an increased extent of sarcomeric organization, as well as an increased activation profile of small GTPases and downstream protein kinases concordant with those seen in vivo. Alendronate attenuated the increase in cell-surface area and BNP mRNA expression induced by Ad-FPPS infection. Additionally, the increased BNP mRNA expression induced by Ad-FPPS infection was attenuated by a RhoA inhibitor C3exoenzyme, but not by FTS.
Conclusions:
Taken together, these results suggest that FPPS may function as a potent regulator in myocardial remodeling. The FPPS-regulated signaling pathway is relevant to the pathological changes in cardiac hypertrophy and HF.
Background:
Angiotensin II (Ang II) is a vasopressor, octapeptide hormone intermediate of the renin-angiotensin system (RAS). Considerable evidence demonstrates Ang II plays a pivotal role in cardiac hypertrophy and fibrosis. In the previous study, we find that the expression level of FPPS is significantly increased in Ang II-treated cardiomyocytes, suggesting that FPPS may play an important role in cardiac hypertrophy induced by Ang II. Our previous work also prove that knockdown of FPPS expression with small interfering RNA or inhibition of FPPS with alendronate prevents Ang II-induced hypertrophy in cultured cardiomyocytes.
Aims:
In this study, we evaluated the effects of FPPS inhibition in Ang II-mediated cardiac hypertrophy and fibrosis in vivo.
Methods:
(1) Wild type mice were separately treated with saline, Ang II (2.88mg/kg per day), FPPS inhibitor alendronate (0.1mg/kg per day), or the combination of Ang II (2.88mg/kg per day) and alendronate (0.1mg/kg per day) for4weeks.
(2) FPPS expression was measured in mice by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot.
(3) FPP and GGPP levels in mice were measured by HPLC.
(4) Cardiac function and morphological changes of mice were investigated by echocardiography, pathological analysis.
(5) ANP, BNP and TGF-β1, Procollagen Ⅰ/Ⅲ mRNA expression in mice were measured by qRT-PCR and ANP and TGF-β1, collagen Ⅰ/Ⅲ protein expression were measured by western blot analysis.
(6) RhoA, Ras activation in mice were measured by G-Lisa method. Besides, the activity of P38mitogen-activated protein kinases (MAPK) was detected by western blot analysis.
Results:
(1) Ang Ⅱ induced cardiac hypertrophy and fibrosis in mice.
(2) Inhibition of FPPS decreased cardiac hypertrophy and fibrosis in Ang Ⅱ-infused mice.
(3) Ang Ⅱ increased FPPS expression and FPPS inhibition decreased p-38MAPK activity in Ang Ⅱ-treated mice.
(4) Inhibition of FPPS decreased ANP, BNP, TGF-β1expression in Ang Ⅱ-infused mice.
(5) Inhibition of FPPS decreased FPP and GGPP levels in Ang Ⅱ-infused mice.
(6) Inhibition of FPPS decreased RhoA activity in Ang Ⅱ-infused mice.
Conclusions:
In conclusion, FPPS might play an important role in Ang Ⅱ-induced cardiac hypertrophy and fibrosis in vivo, at least in part through RhoA, p-38MAPK and TGF-β1.
心肌肥厚和充血性心力衰竭是全世界人类死亡的主要原因之一。心肌肥厚是心力衰竭早期心肌细胞对室壁应力增加的一种重要的适应性、代偿性反应,最终会导致充血性心力衰竭。
法尼基焦磷酸合成酶(famesyl pyrophosphate synthase, FPPS)是甲羟戊酸途径中的一种关键酶,它催化合成异戊二烯化产物,包括法尼基焦磷酸(FPP)和牻牛儿牻牛儿焦磷酸(GGPP)。最新的研究表明FPPS在血管紧张素Ⅱ (Ang Ⅱ)诱导的心肌肥厚细胞中以及自发性高血压大鼠中表达明显增高,同时在自发性高血压大鼠中抑制FPPS可以减轻心肌肥厚和改善血管重塑。这些结果都与RhoA相关,而GGPP对RhoA的牻牛儿牻牛儿焦磷酸化和活化非常重要。
目的：
本研究利用转基因动物模型来进一步探讨FPPS与心肌肥厚和心力衰竭的关系,并研究其机制。
方法：
(1)构建心脏特异性过表达FPPS转基因模型。
(2)使用real-time PCR、western-blot、免疫组化等技术检测转基因小鼠心脏组织中FPPS表达水平。
(3)使用高效液相色谱法(HPLC)技术检测转基因小鼠心脏组织中FPP和GGPP水平,酶法测定组织胆固醇浓度。
(4)使用超声心动图、病理染色、心导管等方法检测转基因小鼠心脏功能及形态学变化。
(5)使用real-time PCR技术检测小鼠心脏心肌肥厚基因(ANP、BNP、β-MHC)以及心肌纤维化基因(TGF-β、CTGF)表达。
(6)使用G-Lisa方法检测小鼠心脏RhoA、Rac1、Cdc42、Ras等小G蛋白表达水平,使用western-blot方法检测小鼠心脏Erk1/2、P38MAPK、 Akt/GSK3β等的活性。
(7)表达FPPS的腺病毒感染心肌细胞,免疫荧光鉴定心肌细胞表面积。FPPS抑制剂阿伦磷酸钠或者Rho的抑制剂C3exoenzyme、Ras抑制剂farnesylthiosalicylic acid (FTS)在感染后加入心肌细胞。
(8)在腺病毒感染的心肌细胞中检测RhoA、Ras、Erk1/2、P38MAPK、 Akt/GSK3β等活性。
(9)使用HPLC技术检测心肌细胞中FPP和GGPP水平,酶法测定细胞胆固醇浓度。
结果：
(1)转基因小鼠心脏组织中FPPS表达明显增加。
(2)心脏特异性表达FPPS增加了FPP和GGPP、胆固醇合成。
(3)心脏特异性表达FPPS诱导心肌肥厚基因(ANP、BNP、β-MHC)、心肌纤维化基因(TGF-β、CTGF)表达增高,最终导致心肌肥厚、纤维化、心力衰竭。
(4)心肌细胞腺病毒过表达FPPS诱导心肌细胞肥厚基因表达、细胞体积增大。心肌细胞中加入阿伦磷酸钠或者C3exoenzyme可抑制FPPS过表达导致的心肌细胞肥大。
(5)心脏特异性表达FPPS诱导RhoA活性增高,磷酸化的ERK和p38表达上调,与体内结果一致,心肌细胞腺病毒过表达FPPS导致RhoA活性增高,磷酸化的ERK和p38表达上调。
结论：
FPPS及FPPS调控的信号转导通路在心肌重塑过程中具有重要的作用。
研究背景：
血管紧张素Ⅱ (AngⅡ)是一种血管加压素,肾素-血管紧张素系统(RAS)的八肽激素中间体。相当多的证据表明,AngⅡ在心肌肥厚和纤维化起着重要的作用。在以往的研究中,我们发现FPPS的表达水平在AngⅡ刺激的肥厚心肌细胞中显著增加,这表明FPPS在AngⅡ引起的心肌肥厚中发挥着重要的作用。另外也研究发现在心肌细胞中通过小分子RNA干扰抑制FPPS基因表达或者药物阿伦磷酸钠抑制FPPS可以阻止AngⅡ诱导的心肌细胞肥大。
目的：
本研究观察抑制FPPS对体内AngⅡ介导的心肌肥厚和纤维化的影响,并探讨其机制。
方法：
(1)野生型小鼠分为四组：生理盐水,血管紧张素Ⅱ(2.88毫克/公斤/天),阿伦磷酸钠(0.1毫克/公斤/天),或血管紧张素Ⅱ(2.88毫克/公斤/天)和阿伦磷酸钠(0.1毫克/公斤/天)持续微泵注射4周。
(2)使用real-time PCR、western-blot等技术检测各组小鼠心脏组织中FPPS表达水平。
(3)使用HPLC技术检测各组小鼠心脏组织中FPP和GGPP水平。
(4)使用超声心动图、病理染色等方法检测各组小鼠心脏功能及形态学变化。
(5)使用real-time PCR技术检测各组小鼠心肌肥厚基因(ANP、BNP)以及心肌纤维化基因(TGF-β1、Procollagen Ⅰ、Procollagen Ⅲ)表达。
(6)使用G-Lisa方法检测RhoA蛋白表达水平, western-blot方法检测P38MAPK的活性。
结果：
(1) AngⅡ诱导小鼠心肌肥厚和纤维化。
(2)抑制FPPS改善AngⅡ诱导的小鼠心肌肥厚和纤维化。
(3) AngⅡ增加FPPS的表达,抑制FPPS减少AngⅡ小鼠中磷酸化P-38的表达。
(4)抑制FPPS降低AngⅡ诱导的ANP, BNP, TGF-β1, Procollagen Ⅰ, Procollagen ⅢmRNA及ANP, TGF-β1, collagen Ⅰ, collagen Ⅲ蛋白表达增加。
(5)抑制FPPS降低AngⅡ诱导的FPP和GGPP水平增加
(6)抑制FPPS减少AngⅡ诱导的RhoA活性增加。
结论：
FPPS在AngⅡ诱导的心肌肥厚和纤维化过程中具有重要的作用,至少部分是通过抑制RhoA的活化,减少p38的磷酸化和下调TGF-β1的表达来实现的。
Background:
Cardiac hypertrophy and heart failure are leading causes of morbidity and mortality worldwide. Cardiac hypertrophy is thought to be an adaptive response to pressure and/or volume overload, which enables the heart to normalize ventricular-wall tension and improve pump function. However, a sustained or excessive hypertrophic response is considered to be maladaptive on the basis of the progression towards heart failure. Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. FPPS catalyzes the synthesis of farnesyl pyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The latter is essential for geranylgeranylation and activation of RhoA. In our previous study we find that inhibition of FPPS attenuates cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and prevents angiotensin (Ang) Ⅱ-induced hypertrophy in cardiomyocytes.
Aims:
We further investigate the role of FPPS in cardiac hypertrophy and heart failure (HF) using transgenic (Tg) model, and its mechanisms.
Methods:
Tg mice with cardiac-specific expression of FPPS were studied as an experimental model.
(1) FPPS expression was measured in Tg mice by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry.
(2) FPP and GGPP levels in Tg mice were measured by HPLC as well as cholesterol concentrations were measured by enzymatic determination.
(3) Cardiac function and morphological changes of Tg mice were investigated by echocardiography, pathological analysis, and cardiac catheterization.
(4) ANP, BNP, β-MHC and TGF-β, CTGF mRNA expression in Tg mice were measured by qRT-PCR.
(5) RhoA, Rac1, Cdc42and Ras activation in Tg mice were measured by G-Lisa method. Besides, the activities of Erkl/2, P38mitogen-activated protein kinases (MAPK) and Akt/GSK3β were detected by western blot analysis.
(6) Areas of cultured neonatal cardiomyocytes infected by adenovirus were detected by immunofluorescence. Alendronate and C3exoenzyme, FTS were added after infection.
(7) RhoA and Ras activation in cardiomyocytes were measured by G-Lisa method. Besides, the activities of Erk1/2, P38MAPK and Akt/GSK3β were detected by western blot analysis.
(8) FPP and GGPP levels in cardiomyocytes were measured by HPLC as well as cholesterol concentration in cardiomyocytes was measured by enzymatic determination.
Results:
(1) FPPS expression was increased in Tg heart.
(2) FPP, GGPP and cholesterol levels were increased in Tg heart.
(3) Tg mice with overexpression of FPPS exhibited cardiac hypertrophy, fibrosis and heart failure as well as enhanced expression of ANP, BNP, β-MHC and TGF-β, CTGF.
(4) These pathological changes were associated with activation of RhoA and other known kinases in the hypertrophic signaling pathways, such as extracellular signal-related kinases1/2(ERK1/2) and p38.
(5) Adenoviral infection of FPPS in cultured neonatal cardiomyocytes induced a hypertrophic response characterized by increased cell size and an increased extent of sarcomeric organization, as well as an increased activation profile of small GTPases and downstream protein kinases concordant with those seen in vivo. Alendronate attenuated the increase in cell-surface area and BNP mRNA expression induced by Ad-FPPS infection. Additionally, the increased BNP mRNA expression induced by Ad-FPPS infection was attenuated by a RhoA inhibitor C3exoenzyme, but not by FTS.
Conclusions:
Taken together, these results suggest that FPPS may function as a potent regulator in myocardial remodeling. The FPPS-regulated signaling pathway is relevant to the pathological changes in cardiac hypertrophy and HF.
Background:
Angiotensin II (Ang II) is a vasopressor, octapeptide hormone intermediate of the renin-angiotensin system (RAS). Considerable evidence demonstrates Ang II plays a pivotal role in cardiac hypertrophy and fibrosis. In the previous study, we find that the expression level of FPPS is significantly increased in Ang II-treated cardiomyocytes, suggesting that FPPS may play an important role in cardiac hypertrophy induced by Ang II. Our previous work also prove that knockdown of FPPS expression with small interfering RNA or inhibition of FPPS with alendronate prevents Ang II-induced hypertrophy in cultured cardiomyocytes.
Aims:
In this study, we evaluated the effects of FPPS inhibition in Ang II-mediated cardiac hypertrophy and fibrosis in vivo.
Methods:
(1) Wild type mice were separately treated with saline, Ang II (2.88mg/kg per day), FPPS inhibitor alendronate (0.1mg/kg per day), or the combination of Ang II (2.88mg/kg per day) and alendronate (0.1mg/kg per day) for4weeks.
(2) FPPS expression was measured in mice by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot.
(3) FPP and GGPP levels in mice were measured by HPLC.
(4) Cardiac function and morphological changes of mice were investigated by echocardiography, pathological analysis.
(5) ANP, BNP and TGF-β1, Procollagen Ⅰ/Ⅲ mRNA expression in mice were measured by qRT-PCR and ANP and TGF-β1, collagen Ⅰ/Ⅲ protein expression were measured by western blot analysis.
(6) RhoA, Ras activation in mice were measured by G-Lisa method. Besides, the activity of P38mitogen-activated protein kinases (MAPK) was detected by western blot analysis.
Results:
(1) Ang Ⅱ induced cardiac hypertrophy and fibrosis in mice.
(2) Inhibition of FPPS decreased cardiac hypertrophy and fibrosis in Ang Ⅱ-infused mice.
(3) Ang Ⅱ increased FPPS expression and FPPS inhibition decreased p-38MAPK activity in Ang Ⅱ-treated mice.
(4) Inhibition of FPPS decreased ANP, BNP, TGF-β1expression in Ang Ⅱ-infused mice.
(5) Inhibition of FPPS decreased FPP and GGPP levels in Ang Ⅱ-infused mice.
(6) Inhibition of FPPS decreased RhoA activity in Ang Ⅱ-infused mice.
Conclusions:
In conclusion, FPPS might play an important role in Ang Ⅱ-induced cardiac hypertrophy and fibrosis in vivo, at least in part through RhoA, p-38MAPK and TGF-β1.
引文
1. Sano M, Schneider MD. Still stressed out but doing fine:Normalization of wall stress is superfluous to maintaining cardiac function in chronic pressure overload. Circulation.2002;105:8-10.
2. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104:1615-1621.
3. Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G. Adaptive and maladaptive hypertrophic pathways:Points of convergence and divergence. Cardiovascular research.2004;63:373-380.
4. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nature reviews. Molecular cell biology.2006;7:589-600.
5. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA. Controversies in ventricular remodelling. Lancet.2006;367:356-367.
6. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. The New England journal of medicine.1999;341:1276-1283.
7. Popjak G, Agnew WS. Squalene synthetase. Molecular and cellular biochemistry. 1979;27:97-116.
8. Liang PH, Ko TP, Wang AH. Structure, mechanism and function of prenyltransferases. European journal of biochemistry/FEBS. 2002;269:3339-3354.
9. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
10. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
11. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999; 103:1627-1634.
12. Ye Y, Mou Y, Bai B, Li L, Chen GP, Hu SJ. Knockdown of farnesylpyrophosphate synthase prevents angiotensin ii-mediated cardiac hypertrophy. The international journal of biochemistry & cell biology.2010;42:2056-2064.
13. Han J, Jiang DM, Du CQ, Hu SJ. Alteration of enzyme expressions in mevalonate pathway:Possible role for cardiovascular remodeling in spontaneously hypertensive rats. Circulation journal:official journal of the Japanese Circulation Society.2011;75:1409-1417.
14. Li L, Hu SJ, Dong HT, Kang L, Chen NY, Fang YQ. Alterations in gene expression of series key enzymes in mevalonic acid pathway detected by rna array in spontaneously hypertensive rats. Chin J Pathophysiol.2008;24:54-59.
15. Li L, Chen GP, Yang Y, Ye Y, Yao L, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. Biochemical pharmacology.2010;79:399-406.
16. Chen GP, Li L, Yang Y, Fu M, Yao L, Wu T, Zhang XQ, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase improves endothelial function in spontaneously hypertensive rats. Biochemical pharmacology.2010;80:1684-1689.
17. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters.2009;583:2997-3003.
18. Richards SM, Jaconi ME, Vassort G, Puceat M. A spliced variant of ael gene encodes a truncated form of band 3 in heart:The predominant anion exchanger in ventricular myocytes. Journal of cell science.1999;112 (Pt 10):1519-1528.
19. Tong H, Wiemer AJ, Neighbors JD, Hohl RJ. Quantitative determination of famesyl and geranylgeranyl diphosphate levels in mammalian tissue. Analytical biochemistry.2008;378:138-143.
20. Tong H, Holstein SA, Hohl RJ. Simultaneous determination of farnesyl and geranylgeranyl pyrophosphate levels in cultured cells. Analytical biochemistry. 2005;336:51-59.
21. Ng WA, Grupp IL, Subramaniam A, Robbins J. Cardiac myosin heavy chain mrna expression and myocardial function in the mouse heart. Circulation research. 1991;68:1742-1750.
22. Laboureau J, Dubertret L, Lebreton-De Coster C, Coulomb B. Erk activation by mechanical strain is regulated by the small g proteins rac-1 and rhoa. Experimental dermatology.2004; 13:70-77.
23. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y. Rho family small g proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circulation research. 1999;84:458-466.
24. Moey M, Rajapurohitam V, Zeidan A, Karmazyn M. Ginseng (panax quinquefolius) attenuates leptin-induced cardiac hypertrophy through inhibition of p115rho guanine nucleotide exchange factor-rhoa/rho-associated, coiled-coil containing protein kinase-dependent mitogen-activated protein kinase pathway activation. The Journal of pharmacology and experimental therapeutics. 2011;339:746-756.
25. Zeidan A, Javadov S, Karmazyn M. Essential role of rho/rock-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovascular research.2006;72:101-111.
26. Hall A. Small gtp-binding proteins and the regulation of the actin cytoskeleton. Annual review of cell biology.1994; 10:31-54.
27. Thorburn A, Thorburn J, Chen SY, Powers S, Shubeita HE, Feramisco JR, Chien KR. Hras-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy. The Journal of biological chemistry. 1993;268:2244-2249.
28. Fuller SJ, Finn SG, Downward J, Sugden PH. Stimulation of gene expression in neonatal rat ventricular myocytes by ras is mediated by ral guanine nucleotide dissociation stimulator (ral.Gds) and phosphatidylinositol 3-kinase in addition to raf. The Biochemical journal.1998;335 (Pt 2):241-246.
29. Oceandy D, Pickard A, Prehar S, Zi M, Mohamed TM, Stanley PJ, Baudoin-Stanley F, Nadif R, Tommasi S, Pfeifer GP, Armesilla AL, Cartwright EJ, Neyses L. Tumor suppressor ras-association domain family 1 isoform a is a novel regulator of cardiac hypertrophy. Circulation.2009; 120:607-616.
30. Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a mlc-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. The Journal of biological chemistry. 1995;270:23173-23178.
31. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews. 2001;81:153-208.
32. Reilly JF, Martinez SD, Mickey G, Maher PA. A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor-mediated signal transduction. The Biochemical journal.2002;366:501-510.
33. Bruenger E, Rilling HC. Determination of isopentenyl diphosphate and farnesyl diphosphate in tissue samples with a comment on secondary regulation of polyisoprenoid biosynthesis. Analytical biochemistry.1988; 173:321-327.
34. Furfine ES, Leban JJ, Landavazo A, Moomaw JF, Casey PJ. Protein farnesyltransferase:Kinetics of farnesyl pyrophosphate binding and product release. Biochemistry.1995;34:6857-6862.
35. Tschantz WR, Furfine ES, Casey PJ. Substrate binding is required for release of product from mammalian protein farnesyltransferase. The Journal of biological chemistry.1997;272:9989-9993.
36. Lu H, Fedak PW, Dai X, Du C, Zhou YQ, Henkelman M, Mongroo PS, Lau A, Yamabi H, Hinek A, Husain M, Hannigan G, Coles JG. Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. Circulation.2006;114:2271-2279.
37. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The mek1-erk1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. The EMBO journal.2000; 19:6341-6350.
38. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD. Takl is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nature medicine.2000;6:556-563.
39. Espada J, Galaz S, Sanz-Rodriguez F, Blazquez-Castro A, Stockert JC, Bagazgoitia L, Jaen P, Gonzalez S, Cano A, Juarranz A. Oncogenic h-ras and pi3k signaling can inhibit e-cadherin-dependent apoptosis and promote cell survival after photodynamic therapy in mouse keratinocytes. Journal of cellular physiology. 2009;219:84-93.
40. Shi GX, Andres DA, Cai W. Ras family small gtpase-mediated neuroprotective signaling in stroke. Central nervous system agents in medicinal chemistry. 2011;11:114-137.
41. Hubchak SC, Runyan CE, Kreisberg JI, Schnaper HW. Cytoskeletal rearrangement and signal transduction in tgf-betal-stimulated mesangial cell collagen accumulation. Journal of the American Society of Nephrology:JASN. 2003;14:1969-1980.
42. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type i/iii ratio. Circulation.1999;99:2750-2756.
43. Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, Schluter KD, Bohm M. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing tgf-beta(1). American journal of physiology. Heart and circulatory physiology.2002;283:H1253-1262.
44. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte tgf-beta signaling in the murine pathological response to sustained pressure overload. The Journal of clinical investigation.2011;121:2301-2312.
45. Ahmed MS, Oie E, Vinge LE, Yndestad A, Oystein Andersen G, Andersson Y, Attramadal T, Attramadal H. Connective tissue growth factor--a novel mediator of angiotensin ii-stimulated cardiac fibroblast activation in heart failure in rats. Journal of molecular and cellular cardiology.2004;36:393-404.
46. Grotendorst GR. Connective tissue growth factor:A mediator of tgf-beta action on fibroblasts. Cytokine & growth factor reviews.1997;8:171-179.
1. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? American journal of physiology. Heart and circulatory physiology.2005;289:H8-H16.
2. Miyajima E, Shigemasa T, Endo T, Hishiki S, Kawano Y. Guanabenz combination therapy inhibits sympathetic nerve activity and regresses left ventricular hypertrophy. Cardiovascular drugs and therapy/sponsored by the International Society of Cardiovascular Pharmacotherapy.2000;14:61-66.
3. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the framingham heart study. The New England journal of medicine. 1990;322:1561-1566.
4. Lorell BH, Carabello BA. Left ventricular hypertrophy:Pathogenesis, detection, and prognosis. Circulation.2000; 102:470-479.
5. Holtz J. Pathophysiology of heart failure and the renin-angiotensin-system. Basic research in cardiology.1993;88 Suppl 1:183-201.
6. Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JS. Angiotensin ii stimulates cardiac myocyte hypertrophy via paracrine release of tgf-beta 1 and endothelin-1 from fibroblasts. Cardiovascular research.1998;40:352-363.
7. Leask A. Potential therapeutic targets for cardiac fibrosis:Tgfbeta, angiotensin, endothelin, ccn2, and pdgf, partners in fibroblast activation. Circulation research.2010;106:1675-1680.
8. Popjak G, Agnew WS. Squalene synthetase. Molecular and cellular biochemistry.1979;27:97-116.
9. Liang PH, Ko TP, Wang AH. Structure, mechanism and function of prenyltransferases. European journal of biochemistry/FEBS. 2002;269:3339-3354.
10. Casey PJ. Protein lipidation in cell signaling. Science.1995;268:221-225.
11. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews.2001;81:153-208.
12. Aikawa R, Komuro I, Nagai R, Yazaki Y. Rho plays an important role in angiotensin ii-induced hypertrophic responses in cardiac myocytes. Molecular and cellular biochemistry.2000;212:177-182.
13. Aoki H, Izumo S, Sadoshima J. Angiotensin ii activates rhoa in cardiac myocytes:A critical role of rhoa in angiotensin ii-induced premyofibril formation. Circulation research.1998;82:666-676.
14. Han J, Jiang DM, Du CQ, Hu SJ. Alteration of enzyme expressions in mevalonate pathway:Possible role for cardiovascular remodeling in spontaneously hypertensive rats. Circulation journal:official journal of the Japanese Circulation Society.2011;75:1409-1417.
15. Li L, Hu SJ, Dong HT, Kang L, Chen NY, Fang YQ. Alterations in gene expression of series key enzymes in mevalonic acid pathway detected by rna array in spontaneously hypertensive rats. Chin J Pathophysiol.2008;24:54-59.
16. Ye Y, Mou Y, Bai B, Li L, Chen GP, Hu SJ. Knockdown of farnesylpyrophosphate synthase prevents angiotensin ii-mediated cardiac hypertrophy. The international journal of biochemistry & cell biology. 2010;42:2056-2064.
17. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters. 2009;583:2997-3003.
18. Nakamura Y, Naito M, Hayashi K, Fotovati A, Abu-Ali S. Effect of combined treatment with alendronate and calcitriol on femoral neck strength in osteopenic rats. Journal of orthopaedic surgery and research.2008;3:51.
19. Stabnov L, Kasukawa Y, Guo R, Amaar Y, Wergedal JE, Baylink DJ, Mohan S. Effect of insulin-like growth factor-1 (igf-1) plus alendronate on bone density during puberty in igf-1-deficient midi mice. Bone.2002;30:909-916.
20. Ho TJ, Huang CC, Huang CY, Lin WT. Fasudil, a rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats. European journal of applied physiology. 2012;112:2943-2955.
21. Moey M, Rajapurohitam V, Zeidan A, Karmazyn M. Ginseng (panax quinquefolius) attenuates leptin-induced cardiac hypertrophy through inhibition of p115rho guanine nucleotide exchange factor-rhoa/rho-associated, coiled-coil containing protein kinase-dependent mitogen-activated protein kinase pathway activation. The Journal of pharmacology and experimental therapeutics. 2011;339:746-756.
22. Zeidan A, Javadov S, Karmazyn M. Essential role of rho/rock-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovascular research.2006;72:101-111.
23. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. The New England journal of medicine.1994;331:1286-1292.
24. Moriguchi Y, Matsubara H, Mori Y, Murasawa S, Masaki H, Maruyama K, Tsutsumi Y, Shibasaki Y, Tanaka Y, Nakajima T, Oda K, Iwasaka T. Angiotensin ii-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circulation research.1999;84:1073-1084.
25. McTaggart SJ. Isoprenylated proteins. Cellular and molecular life sciences: CMLS.2006;63:255-267.
26. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H. Angiotensin ii induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension.1995;25:1252-1259.
27. Hall A. Small gtp-binding proteins and the regulation of the actin cytoskeleton. Annual review of cell biology.1994; 10:31-54.
28. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y. Rho family small g proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circulation research.1999;84:458-466.
29. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
30. Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira, Ⅱ, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldshmidt-Clermont PJ, Irani K, Finkel T. A requirement for the rac1 gtpase in the signal transduction pathway leading to cardiac myocyte hypertrophy. The Journal of clinical investigation. 1998; 102:929-937.
31. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
32. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999;103:1627-1634.
33. Kobayashi N, Nakano S, Mita S, Kobayashi T, Honda T, Tsubokou Y, Matsuoka H. Involvement of rho-kinase pathway for angiotensin ii-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats. The Journal of pharmacology and experimental therapeutics. 2002;301:459-466.
34. Li L, Chen GP, Yang Y, Ye Y, Yao L, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. Biochemical pharmacology.2010;79:399-406.
35. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD. Takl is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nature medicine.2000;6:556-563.
36. Zeidan A, Javadov S, Chakrabarti S, Karmazyn M. Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and rhoa/rock-dependent p38 mapk translocation to nuclei. Cardiovascular research. 2008;77:64-72.
37. Hubchak SC, Runyan CE, Kreisberg JI, Schnaper HW. Cytoskeletal rearrangement and signal transduction in tgf-betal-stimulated mesangial cell collagen accumulation. Journal of the American Society of Nephrology:JASN. 2003;14:1969-1980.
38. Ishikawa Y, Nishikimi T, Akimoto K, Ishimura K, Ono H, Matsuoka H. Long-term administration of rho-kinase inhibitor ameliorates renal damage in malignant hypertensive rats. Hypertension.2006;47:1075-1083.
39. Brilla CG. Renin-angiotensin-aldosterone system and myocardial fibrosis. Cardiovascular research.2000;47:1-3.
40. Ichihara S, Senbonmatsu T, Price E, Jr., Ichiki T, Gaffney FA, Inagami T. Angiotensin ii type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin ii-induced hypertension. Circulation. 2001;104:346-351.
41. Ju H, Dixon IM. Effect of angiotensin ii on myocardial collagen gene expression. Molecular and cellular biochemistry.1996;163-164:231-237.
42. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type i/iii ratio. Circulation.1999;99:2750-2756.
43. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of transforming growth factor-beta via angiotensin ii type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension.1998;32:273-279.
44. Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, Schluter KD, Bohm M. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing tgf-beta(1). American journal of physiology. Heart and circulatory physiology.2002;283:H1253-1262.
45. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte tgf-beta signaling in the murine pathological response to sustained pressure overload. The Journal of clinical investigation.2011;121:2301-2312.
46. Kagiyama S, Eguchi S, Frank GD, Inagami T, Zhang YC, Phillips MI. Angiotensin ii-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense. Circulation.2002;106:909-912.
47. Patiag D, Qu X, Gray S, Idris I, Wilkes M, Seale JP, Donnelly R. Possible interactions between angiotensin ii and insulin:Effects on glucose and lipid metabolism in vivo and in vitro. The Journal of endocrinology. 2000;167:525-531.
48. Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Katagiri H, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Komuro I, Fujita T. Angiotensin ii-induced insulin resistance is associated with enhanced insulin signaling. Hypertension.2002;40:872-879.
49. Mascareno E, Dhar M, Siddiqui MA. Signal transduction and activator of transcription (stat) protein-dependent activation of angiotensinogen promoter: A cellular signal for hypertrophy in cardiac muscle. Proceedings of the National Academy of Sciences of the United States of America.1998;95:5590-5594.
50. Omura T, Yoshiyama M, Ishikura F, Kobayashi H, Takeuchi K, Beppu S, Yoshikawa J. Myocardial ischemia activates the jak-stat pathway through angiotensin ii signaling in in vivo myocardium of rats. Journal of molecular and cellular cardiology.2001;33:307-316.
51. Sadoshima J, Izumo S. The heterotrimeric g q protein-coupled angiotensin ii receptor activates p21 ras via the tyrosine kinase-shc-grb2-sos pathway in cardiac myocytes. The EMBO journal.1996;15:775-787.
1. Sugden PH, Clerk A.Cellular mechanisms of cardiac hypertrophy. J Mol Med (Berl).1998;76:725-746.
2. Wennerberg K, Rossman KL, Der CJ. The ras superfamily at a glance. Journal of cell science.2005;118:843-846.
3. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews. 2001;81:153-208.
4. Adamson P, Marshall CJ, Hall A, Tilbrook PA. Post-translational modifications of p21rho proteins. The Journal of biological chemistry.1992;267:20033-20038.
5. Bos JL, Rehmann H, Wittinghofer A. Gefs and gaps:Critical elements in the control of small g proteins. Cell.2007;129:865-877.
6. Bhattacharya M, Babwah AV, Ferguson SS. Small gtp-binding protein-coupled receptors. Biochemical Society transactions.2004;32:1040-1044.
7. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure:The framingham study. Journal of the American College of Cardiology. 1993;22:6A-13A.
8. Vojtek AB, Der CJ. Increasing complexity of the ras signaling pathway. The Journal of biological chemistry.1998;273:19925-19928.
9. Aspenstrom P. Effectors for the rho gtpases. Current opinion in cell biology. 1999; 11:95-102.
10. Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the rho family gtpases in mammalian cells. Annual review of biochemistry.1999;68:459-486.
11. Bagrodia S, Cerione RA. Pak to the future. Trends in cell biology.1999;9:350-355.
12. Sugden PH, Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-jun n-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circulation research.1998;83:345-352.
13. Chiloeches A, Paterson HF, Marais R, Clerk A, Marshall CJ, Sugden PH. Regulation of ras.Gtp loading and ras-raf association in neonatal rat ventricular myocytes by g protein-coupled receptor agonists and phorbol ester. Activation of the extracellular signal-regulated kinase cascade by phorbol ester is mediated by ras. The Journal of biological chemistry.1999;274:19762-19770.
14. Thorburn A, Thorburn J, Chen SY, Powers S, Shubeita HE, Feramisco JR, Chien KR. Hras-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy. The Journal of biological chemistry. 1993;268:2244-2249.
15. Abdellatif M, Schneider MD. An effector-like function of ras gtpase-activating protein predominates in cardiac muscle cells. The Journal of biological chemistry. 1997;272:525-533.
16. Fuller SJ, Finn SG, Downward J, Sugden PH. Stimulation of gene expression in neonatal rat ventricular myocytes by ras is mediated by ral guanine nucleotide dissociation stimulator (ral.Gds) and phosphatidylinositol 3-kinase in addition to raf. The Biochemical journal.1998;335 (Pt 2):241-246.
17. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
18. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
19. Thorburn J, Xu S, Thorburn A. Map kinase- and rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. The EMBO journal.1997; 16:1888-1900.
20. Aoki H, Izumo S, Sadoshima J. Angiotensin ii activates rhoa in cardiac myocytes: A critical role of rhoa in angiotensin ii-induced premyofibril formation. Circulation research.1998;82:666-676.
21. Hines WA, Thorburn A. Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytes. Journal of molecular and cellular cardiology.1998;30:485-494.
22. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters.2009;583:2997-3003.
23. Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. The Journal of cell biology.1997;139:115-127.
24. Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira, II, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldshmidt-Clermont PJ, Irani K, Finkel T. A requirement for the racl gtpase in the signal transduction pathway leading to cardiac myocyte hypertrophy. The Journal of clinical investigation. 1998;102:929-937.
25. Izumo S, Shioi T. Cardiac transgenic and gene-targeted mice as models of cardiac hypertrophy and failure:A problem of (new) riches. Journal of cardiac failure. 1998;4:263-270.
26. Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a mlc-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. The Journal of biological chemistry. 1995;270:23173-23178.
27. Zheng M, Dilly K, Dos Santos Cruz J, Li M, Gu Y, Ursitti JA, Chen J, Ross J, Jr., Chien KR, Lederer JW, Wang Y. Sarcoplasmic reticulum calcium defect in ras-induced hypertrophic cardiomyopathy heart. American journal of physiology. Heart and circulatory physiology.2004;286:H424-433.
28. Kai H, Muraishi A, Sugiu Y, Nishi H, Seki Y, Kuwahara F, Kimura A, Kato H, Imaizumi T. Expression of proto-oncogenes and gene mutation of sarcomeric proteins in patients with hypertrophic cardiomyopathy. Circulation research. 1998;83:594-601.
29. Ruan H, Mitchell S, Vainoriene M, Lou Q, Xie LH, Ren S, Goldhaber JI, Wang Y. Gi alpha 1-mediated cardiac electrophysiological remodeling and arrhythmia in hypertrophic cardiomyopathy. Circulation.2007;116:596-605.
30. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999; 103:1627-1634.
31. Cachero TG, Morielli AD, Peralta EG The small gtp-binding protein rhoa regulates a delayed rectifier potassium channel. Cell.1998;93:1077-1085.
32. Yatani A, Irie K, Otani T, Abdellatif M, Wei L. Rhoa gtpase regulates 1-type ca2+ currents in cardiac myocytes. American journal of physiology. Heart and circulatory physiology.2005;288:H650-659.
33. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation.2001;104:317-324.
34. Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in rockl+/-haploinsufficient mice. Circulation.2005; 112:2959-2965.
35. Wei L, Imanaka-Yoshida K, Wang L, Zhan S, Schneider MD, DeMayo FJ, Schwartz RJ. Inhibition of rho family gtpases by rho gdp dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation. Development.2002;129:1705-1714.
36. Wei L, Taffet GE, Khoury DS, Bo J, Li Y, Yatani A, Delaughter MC, Klevitsky R, Hewett TE, Robbins J, Michael LH, Schneider MD, Entman ML, Schwartz RJ. Disruption of rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved. FASEB journal:official publication of the Federation of American Societies for Experimental Biology. 2004;18:857-859.
37. Satoh M, Ogita H, Takeshita K, Mukai Y, Kwiatkowski DJ, Liao JK. Requirement of racl in the development of cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America.2006; 103:7432-7437.
38. Lu H, Fedak PW, Dai X, Du C, Zhou YQ, Henkelman M, Mongroo PS, Lau A, Yamabi H, Hinek A, Husain M, Hannigan G, Coles JG. Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. Circulation.2006; 114:2271-2279.
39. Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E, Yager K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. The Journal of clinical investigation. 2000;105:875-886.
40. Buscemi N, Murray C, Doherty-Kirby A, Lajoie G, Sussman MA, Van Eyk JE. Myocardial subproteomic analysis of a constitutively active racl-expressing transgenic mouse with lethal myocardial hypertrophy. American journal of physiology. Heart and circulatory physiology.2005;289:H2325-2333.
41. Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G Impact of hmg coa reductase inhibition on small gtpases in the heart. Cardiovascular research. 2002;53:911-920.
42. Ramirez MT, Sah VP, Zhao XL, Hunter JJ, Chien KR, Brown JH. The mekk-jnk pathway is stimulated by alphal-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy. The Journal of biological chemistry.1997;272:14057-14061.
43. Muslin AJ. Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. Trends in cardiovascular medicine.2005; 15:225-229.
44. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, Sugden PH. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. Journal of cellular physiology. 2007;212:311-322.
45. Proud CG. Ras, pi3-kinase and mtor signaling in cardiac hypertrophy. Cardiovascular research.2004;63:403-413.
46. Morissette MR, Sah VP, Glembotski CC, Brown JH. The rho effector, pkn, regulates anf gene transcription in cardiomyocytes through a serum response element. American journal of physiology. Heart and circulatory physiology. 2000;278:H1769-1774.
47. Satoh S, Ueda Y, Koyanagi M, Kadokami T, Sugano M, Yoshikawa Y, Makino N. Chronic inhibition of rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. Journal of molecular and cellular cardiology.2003;35:59-70.
48. Clerk A, Pham FH, Fuller SJ, Sahai E, Aktories K, Marais R, Marshall C, Sugden PH. Regulation of mitogen-activated protein kinases in cardiac myocytes through the small g protein rac1. Molecular and cellular biology.2001;21:1173-1184.
49. Kawamura S, Miyamoto S, Brown JH. Initiation and transduction of stretch-induced rhoa and racl activation through caveolae:Cytoskeletal regulation of erk translocation. The Journal of biological chemistry.2003;278:31111-31117.
50. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circulation research.2006;98:322-334.
51. Kuwahara K, Saito Y, Nakagawa O, Kishimoto I, Harada M, Ogawa E, Miyamoto Y, Hamanaka I, Kajiyama N, Takahashi N, Izumi T, Kawakami R, Tamura N, Ogawa Y, Nakao K. The effects of the selective rock inhibitor, y27632, on et-1-induced hypertrophic response in neonatal rat cardiac myocytes--possible involvement of rho/rock pathway in cardiac muscle cell hypertrophy. FEBS letters. 1999;452:314-318.
52. Yanazume T, Hasegawa K, Wada H, Morimoto T, Abe M, Kawamura T, Sasayama S. Rho/rock pathway contributes to the activation of extracellular signal-regulated kinase/gata-4 during myocardial cell hypertrophy. The Journal of biological chemistry.2002;277:8618-8625.
53. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K, Takeshita A. Long-term treatment with a specific rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circulation research.2004;94:46-52.
54. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A. Long-term inhibition of rho-kinase suppresses angiotensin ii-induced cardiovascular hypertrophy in rats in vivo:Effect on endothelial nad(p)h oxidase system. Circulation research.2003;93:767-775.
55. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. The Journal of clinical investigation.2001;108:1429-1437.
56. Higuchi Y, Otsu K, Nishida K, Hirotani S, Nakayama H, Yamaguchi O, Hikoso S, Kashiwase K, Takeda T, Watanabe T, Mano T, Matsumura Y, Ueno H, Hori M. The small gtp-binding protein rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear factor-kappa b. The Journal of biological chemistry.2003;278:20770-20777.
57. Maillet M, Lynch JM, Sanna B, York AJ, Zheng Y, Molkentin JD. Cdc42 is an antihypertrophic molecular switch in the mouse heart. The Journal of clinical investigation.2009; 119:3079-3088.
58. Li JM, Gall NP, Grieve DJ, Chen M, Shah AM. Activation of nadph oxidase during progression of cardiac hypertrophy to failure. Hypertension. 2002;40:477-484.
59. MacCarthy PA, Grieve DJ, Li JM, Dunster C, Kelly FJ, Shah AM. Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy:Role of reactive oxygen species and nadph oxidase. Circulation.2001;104:2967-2974.
60. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of a gp91(phox)-containing nadph oxidase in angiotensin ii-induced cardiac hypertrophy in mice. Circulation.2002; 105:293-296.
61. Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB. Role of reactive oxygen species and nad(p)h oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. American journal of physiology. Cell physiology. 2002;282:C926-934.
62. Odley A, Hahn HS, Lynch RA, Marreez Y, Osinska H, Robbins J, Dorn GW,2nd. Regulation of cardiac contractility by rab4-modulated beta2-adrenergic receptor recycling. Proceedings of the National Academy of Sciences of the United States of America.2004; 101:7082-7087.
63. Filipeanu CM, Zhou F, Lam ML, Kerut KE, Claycomb WC, Wu G. Enhancement of the recycling and activation of beta-adrenergic receptor by rab4 gtpase in cardiac myocytes. The Journal of biological chemistry.2006;281:11097-11103.
64. Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M, Adachi T, Ogawa S, Fukuda K. Dominant negative suppression of rad leads to qt prolongation and causes ventricular arrhythmias via modulation of 1-type ca2+ channels in the heart. Circulation research.2007; 101:69-77.
65. Chang L, Zhang J, Tseng YH, Xie CQ, Ilany J, Bruning JC, Sun Z, Zhu X, Cui T, Youker KA, Yang Q, Day SM, Kahn CR, Chen YE. Rad gtpase deficiency leads to cardiac hypertrophy. Circulation.2007; 116:2976-2983.
2. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104:1615-1621.
3. Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G. Adaptive and maladaptive hypertrophic pathways:Points of convergence and divergence. Cardiovascular research.2004;63:373-380.
4. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nature reviews. Molecular cell biology.2006;7:589-600.
5. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA. Controversies in ventricular remodelling. Lancet.2006;367:356-367.
6. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. The New England journal of medicine.1999;341:1276-1283.
7. Popjak G, Agnew WS. Squalene synthetase. Molecular and cellular biochemistry. 1979;27:97-116.
8. Liang PH, Ko TP, Wang AH. Structure, mechanism and function of prenyltransferases. European journal of biochemistry/FEBS. 2002;269:3339-3354.
9. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
10. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
11. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999; 103:1627-1634.
12. Ye Y, Mou Y, Bai B, Li L, Chen GP, Hu SJ. Knockdown of farnesylpyrophosphate synthase prevents angiotensin ii-mediated cardiac hypertrophy. The international journal of biochemistry & cell biology.2010;42:2056-2064.
13. Han J, Jiang DM, Du CQ, Hu SJ. Alteration of enzyme expressions in mevalonate pathway:Possible role for cardiovascular remodeling in spontaneously hypertensive rats. Circulation journal:official journal of the Japanese Circulation Society.2011;75:1409-1417.
14. Li L, Hu SJ, Dong HT, Kang L, Chen NY, Fang YQ. Alterations in gene expression of series key enzymes in mevalonic acid pathway detected by rna array in spontaneously hypertensive rats. Chin J Pathophysiol.2008;24:54-59.
15. Li L, Chen GP, Yang Y, Ye Y, Yao L, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. Biochemical pharmacology.2010;79:399-406.
16. Chen GP, Li L, Yang Y, Fu M, Yao L, Wu T, Zhang XQ, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase improves endothelial function in spontaneously hypertensive rats. Biochemical pharmacology.2010;80:1684-1689.
17. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters.2009;583:2997-3003.
18. Richards SM, Jaconi ME, Vassort G, Puceat M. A spliced variant of ael gene encodes a truncated form of band 3 in heart:The predominant anion exchanger in ventricular myocytes. Journal of cell science.1999;112 (Pt 10):1519-1528.
19. Tong H, Wiemer AJ, Neighbors JD, Hohl RJ. Quantitative determination of famesyl and geranylgeranyl diphosphate levels in mammalian tissue. Analytical biochemistry.2008;378:138-143.
20. Tong H, Holstein SA, Hohl RJ. Simultaneous determination of farnesyl and geranylgeranyl pyrophosphate levels in cultured cells. Analytical biochemistry. 2005;336:51-59.
21. Ng WA, Grupp IL, Subramaniam A, Robbins J. Cardiac myosin heavy chain mrna expression and myocardial function in the mouse heart. Circulation research. 1991;68:1742-1750.
22. Laboureau J, Dubertret L, Lebreton-De Coster C, Coulomb B. Erk activation by mechanical strain is regulated by the small g proteins rac-1 and rhoa. Experimental dermatology.2004; 13:70-77.
23. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y. Rho family small g proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circulation research. 1999;84:458-466.
24. Moey M, Rajapurohitam V, Zeidan A, Karmazyn M. Ginseng (panax quinquefolius) attenuates leptin-induced cardiac hypertrophy through inhibition of p115rho guanine nucleotide exchange factor-rhoa/rho-associated, coiled-coil containing protein kinase-dependent mitogen-activated protein kinase pathway activation. The Journal of pharmacology and experimental therapeutics. 2011;339:746-756.
25. Zeidan A, Javadov S, Karmazyn M. Essential role of rho/rock-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovascular research.2006;72:101-111.
26. Hall A. Small gtp-binding proteins and the regulation of the actin cytoskeleton. Annual review of cell biology.1994; 10:31-54.
27. Thorburn A, Thorburn J, Chen SY, Powers S, Shubeita HE, Feramisco JR, Chien KR. Hras-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy. The Journal of biological chemistry. 1993;268:2244-2249.
28. Fuller SJ, Finn SG, Downward J, Sugden PH. Stimulation of gene expression in neonatal rat ventricular myocytes by ras is mediated by ral guanine nucleotide dissociation stimulator (ral.Gds) and phosphatidylinositol 3-kinase in addition to raf. The Biochemical journal.1998;335 (Pt 2):241-246.
29. Oceandy D, Pickard A, Prehar S, Zi M, Mohamed TM, Stanley PJ, Baudoin-Stanley F, Nadif R, Tommasi S, Pfeifer GP, Armesilla AL, Cartwright EJ, Neyses L. Tumor suppressor ras-association domain family 1 isoform a is a novel regulator of cardiac hypertrophy. Circulation.2009; 120:607-616.
30. Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a mlc-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. The Journal of biological chemistry. 1995;270:23173-23178.
31. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews. 2001;81:153-208.
32. Reilly JF, Martinez SD, Mickey G, Maher PA. A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor-mediated signal transduction. The Biochemical journal.2002;366:501-510.
33. Bruenger E, Rilling HC. Determination of isopentenyl diphosphate and farnesyl diphosphate in tissue samples with a comment on secondary regulation of polyisoprenoid biosynthesis. Analytical biochemistry.1988; 173:321-327.
34. Furfine ES, Leban JJ, Landavazo A, Moomaw JF, Casey PJ. Protein farnesyltransferase:Kinetics of farnesyl pyrophosphate binding and product release. Biochemistry.1995;34:6857-6862.
35. Tschantz WR, Furfine ES, Casey PJ. Substrate binding is required for release of product from mammalian protein farnesyltransferase. The Journal of biological chemistry.1997;272:9989-9993.
36. Lu H, Fedak PW, Dai X, Du C, Zhou YQ, Henkelman M, Mongroo PS, Lau A, Yamabi H, Hinek A, Husain M, Hannigan G, Coles JG. Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. Circulation.2006;114:2271-2279.
37. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The mek1-erk1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. The EMBO journal.2000; 19:6341-6350.
38. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD. Takl is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nature medicine.2000;6:556-563.
39. Espada J, Galaz S, Sanz-Rodriguez F, Blazquez-Castro A, Stockert JC, Bagazgoitia L, Jaen P, Gonzalez S, Cano A, Juarranz A. Oncogenic h-ras and pi3k signaling can inhibit e-cadherin-dependent apoptosis and promote cell survival after photodynamic therapy in mouse keratinocytes. Journal of cellular physiology. 2009;219:84-93.
40. Shi GX, Andres DA, Cai W. Ras family small gtpase-mediated neuroprotective signaling in stroke. Central nervous system agents in medicinal chemistry. 2011;11:114-137.
41. Hubchak SC, Runyan CE, Kreisberg JI, Schnaper HW. Cytoskeletal rearrangement and signal transduction in tgf-betal-stimulated mesangial cell collagen accumulation. Journal of the American Society of Nephrology:JASN. 2003;14:1969-1980.
42. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type i/iii ratio. Circulation.1999;99:2750-2756.
43. Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, Schluter KD, Bohm M. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing tgf-beta(1). American journal of physiology. Heart and circulatory physiology.2002;283:H1253-1262.
44. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte tgf-beta signaling in the murine pathological response to sustained pressure overload. The Journal of clinical investigation.2011;121:2301-2312.
45. Ahmed MS, Oie E, Vinge LE, Yndestad A, Oystein Andersen G, Andersson Y, Attramadal T, Attramadal H. Connective tissue growth factor--a novel mediator of angiotensin ii-stimulated cardiac fibroblast activation in heart failure in rats. Journal of molecular and cellular cardiology.2004;36:393-404.
46. Grotendorst GR. Connective tissue growth factor:A mediator of tgf-beta action on fibroblasts. Cytokine & growth factor reviews.1997;8:171-179.
1. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? American journal of physiology. Heart and circulatory physiology.2005;289:H8-H16.
2. Miyajima E, Shigemasa T, Endo T, Hishiki S, Kawano Y. Guanabenz combination therapy inhibits sympathetic nerve activity and regresses left ventricular hypertrophy. Cardiovascular drugs and therapy/sponsored by the International Society of Cardiovascular Pharmacotherapy.2000;14:61-66.
3. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the framingham heart study. The New England journal of medicine. 1990;322:1561-1566.
4. Lorell BH, Carabello BA. Left ventricular hypertrophy:Pathogenesis, detection, and prognosis. Circulation.2000; 102:470-479.
5. Holtz J. Pathophysiology of heart failure and the renin-angiotensin-system. Basic research in cardiology.1993;88 Suppl 1:183-201.
6. Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JS. Angiotensin ii stimulates cardiac myocyte hypertrophy via paracrine release of tgf-beta 1 and endothelin-1 from fibroblasts. Cardiovascular research.1998;40:352-363.
7. Leask A. Potential therapeutic targets for cardiac fibrosis:Tgfbeta, angiotensin, endothelin, ccn2, and pdgf, partners in fibroblast activation. Circulation research.2010;106:1675-1680.
8. Popjak G, Agnew WS. Squalene synthetase. Molecular and cellular biochemistry.1979;27:97-116.
9. Liang PH, Ko TP, Wang AH. Structure, mechanism and function of prenyltransferases. European journal of biochemistry/FEBS. 2002;269:3339-3354.
10. Casey PJ. Protein lipidation in cell signaling. Science.1995;268:221-225.
11. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews.2001;81:153-208.
12. Aikawa R, Komuro I, Nagai R, Yazaki Y. Rho plays an important role in angiotensin ii-induced hypertrophic responses in cardiac myocytes. Molecular and cellular biochemistry.2000;212:177-182.
13. Aoki H, Izumo S, Sadoshima J. Angiotensin ii activates rhoa in cardiac myocytes:A critical role of rhoa in angiotensin ii-induced premyofibril formation. Circulation research.1998;82:666-676.
14. Han J, Jiang DM, Du CQ, Hu SJ. Alteration of enzyme expressions in mevalonate pathway:Possible role for cardiovascular remodeling in spontaneously hypertensive rats. Circulation journal:official journal of the Japanese Circulation Society.2011;75:1409-1417.
15. Li L, Hu SJ, Dong HT, Kang L, Chen NY, Fang YQ. Alterations in gene expression of series key enzymes in mevalonic acid pathway detected by rna array in spontaneously hypertensive rats. Chin J Pathophysiol.2008;24:54-59.
16. Ye Y, Mou Y, Bai B, Li L, Chen GP, Hu SJ. Knockdown of farnesylpyrophosphate synthase prevents angiotensin ii-mediated cardiac hypertrophy. The international journal of biochemistry & cell biology. 2010;42:2056-2064.
17. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters. 2009;583:2997-3003.
18. Nakamura Y, Naito M, Hayashi K, Fotovati A, Abu-Ali S. Effect of combined treatment with alendronate and calcitriol on femoral neck strength in osteopenic rats. Journal of orthopaedic surgery and research.2008;3:51.
19. Stabnov L, Kasukawa Y, Guo R, Amaar Y, Wergedal JE, Baylink DJ, Mohan S. Effect of insulin-like growth factor-1 (igf-1) plus alendronate on bone density during puberty in igf-1-deficient midi mice. Bone.2002;30:909-916.
20. Ho TJ, Huang CC, Huang CY, Lin WT. Fasudil, a rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats. European journal of applied physiology. 2012;112:2943-2955.
21. Moey M, Rajapurohitam V, Zeidan A, Karmazyn M. Ginseng (panax quinquefolius) attenuates leptin-induced cardiac hypertrophy through inhibition of p115rho guanine nucleotide exchange factor-rhoa/rho-associated, coiled-coil containing protein kinase-dependent mitogen-activated protein kinase pathway activation. The Journal of pharmacology and experimental therapeutics. 2011;339:746-756.
22. Zeidan A, Javadov S, Karmazyn M. Essential role of rho/rock-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovascular research.2006;72:101-111.
23. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. The New England journal of medicine.1994;331:1286-1292.
24. Moriguchi Y, Matsubara H, Mori Y, Murasawa S, Masaki H, Maruyama K, Tsutsumi Y, Shibasaki Y, Tanaka Y, Nakajima T, Oda K, Iwasaka T. Angiotensin ii-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circulation research.1999;84:1073-1084.
25. McTaggart SJ. Isoprenylated proteins. Cellular and molecular life sciences: CMLS.2006;63:255-267.
26. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H. Angiotensin ii induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension.1995;25:1252-1259.
27. Hall A. Small gtp-binding proteins and the regulation of the actin cytoskeleton. Annual review of cell biology.1994; 10:31-54.
28. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y. Rho family small g proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circulation research.1999;84:458-466.
29. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
30. Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira, Ⅱ, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldshmidt-Clermont PJ, Irani K, Finkel T. A requirement for the rac1 gtpase in the signal transduction pathway leading to cardiac myocyte hypertrophy. The Journal of clinical investigation. 1998; 102:929-937.
31. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
32. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999;103:1627-1634.
33. Kobayashi N, Nakano S, Mita S, Kobayashi T, Honda T, Tsubokou Y, Matsuoka H. Involvement of rho-kinase pathway for angiotensin ii-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats. The Journal of pharmacology and experimental therapeutics. 2002;301:459-466.
34. Li L, Chen GP, Yang Y, Ye Y, Yao L, Hu SJ. Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. Biochemical pharmacology.2010;79:399-406.
35. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD. Takl is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nature medicine.2000;6:556-563.
36. Zeidan A, Javadov S, Chakrabarti S, Karmazyn M. Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and rhoa/rock-dependent p38 mapk translocation to nuclei. Cardiovascular research. 2008;77:64-72.
37. Hubchak SC, Runyan CE, Kreisberg JI, Schnaper HW. Cytoskeletal rearrangement and signal transduction in tgf-betal-stimulated mesangial cell collagen accumulation. Journal of the American Society of Nephrology:JASN. 2003;14:1969-1980.
38. Ishikawa Y, Nishikimi T, Akimoto K, Ishimura K, Ono H, Matsuoka H. Long-term administration of rho-kinase inhibitor ameliorates renal damage in malignant hypertensive rats. Hypertension.2006;47:1075-1083.
39. Brilla CG. Renin-angiotensin-aldosterone system and myocardial fibrosis. Cardiovascular research.2000;47:1-3.
40. Ichihara S, Senbonmatsu T, Price E, Jr., Ichiki T, Gaffney FA, Inagami T. Angiotensin ii type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin ii-induced hypertension. Circulation. 2001;104:346-351.
41. Ju H, Dixon IM. Effect of angiotensin ii on myocardial collagen gene expression. Molecular and cellular biochemistry.1996;163-164:231-237.
42. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP. Dilated cardiomyopathy is associated with significant changes in collagen type i/iii ratio. Circulation.1999;99:2750-2756.
43. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of transforming growth factor-beta via angiotensin ii type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension.1998;32:273-279.
44. Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, Schluter KD, Bohm M. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing tgf-beta(1). American journal of physiology. Heart and circulatory physiology.2002;283:H1253-1262.
45. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte tgf-beta signaling in the murine pathological response to sustained pressure overload. The Journal of clinical investigation.2011;121:2301-2312.
46. Kagiyama S, Eguchi S, Frank GD, Inagami T, Zhang YC, Phillips MI. Angiotensin ii-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense. Circulation.2002;106:909-912.
47. Patiag D, Qu X, Gray S, Idris I, Wilkes M, Seale JP, Donnelly R. Possible interactions between angiotensin ii and insulin:Effects on glucose and lipid metabolism in vivo and in vitro. The Journal of endocrinology. 2000;167:525-531.
48. Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Katagiri H, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Komuro I, Fujita T. Angiotensin ii-induced insulin resistance is associated with enhanced insulin signaling. Hypertension.2002;40:872-879.
49. Mascareno E, Dhar M, Siddiqui MA. Signal transduction and activator of transcription (stat) protein-dependent activation of angiotensinogen promoter: A cellular signal for hypertrophy in cardiac muscle. Proceedings of the National Academy of Sciences of the United States of America.1998;95:5590-5594.
50. Omura T, Yoshiyama M, Ishikura F, Kobayashi H, Takeuchi K, Beppu S, Yoshikawa J. Myocardial ischemia activates the jak-stat pathway through angiotensin ii signaling in in vivo myocardium of rats. Journal of molecular and cellular cardiology.2001;33:307-316.
51. Sadoshima J, Izumo S. The heterotrimeric g q protein-coupled angiotensin ii receptor activates p21 ras via the tyrosine kinase-shc-grb2-sos pathway in cardiac myocytes. The EMBO journal.1996;15:775-787.
1. Sugden PH, Clerk A.Cellular mechanisms of cardiac hypertrophy. J Mol Med (Berl).1998;76:725-746.
2. Wennerberg K, Rossman KL, Der CJ. The ras superfamily at a glance. Journal of cell science.2005;118:843-846.
3. Takai Y, Sasaki T, Matozaki T. Small gtp-binding proteins. Physiological reviews. 2001;81:153-208.
4. Adamson P, Marshall CJ, Hall A, Tilbrook PA. Post-translational modifications of p21rho proteins. The Journal of biological chemistry.1992;267:20033-20038.
5. Bos JL, Rehmann H, Wittinghofer A. Gefs and gaps:Critical elements in the control of small g proteins. Cell.2007;129:865-877.
6. Bhattacharya M, Babwah AV, Ferguson SS. Small gtp-binding protein-coupled receptors. Biochemical Society transactions.2004;32:1040-1044.
7. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure:The framingham study. Journal of the American College of Cardiology. 1993;22:6A-13A.
8. Vojtek AB, Der CJ. Increasing complexity of the ras signaling pathway. The Journal of biological chemistry.1998;273:19925-19928.
9. Aspenstrom P. Effectors for the rho gtpases. Current opinion in cell biology. 1999; 11:95-102.
10. Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the rho family gtpases in mammalian cells. Annual review of biochemistry.1999;68:459-486.
11. Bagrodia S, Cerione RA. Pak to the future. Trends in cell biology.1999;9:350-355.
12. Sugden PH, Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-jun n-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circulation research.1998;83:345-352.
13. Chiloeches A, Paterson HF, Marais R, Clerk A, Marshall CJ, Sugden PH. Regulation of ras.Gtp loading and ras-raf association in neonatal rat ventricular myocytes by g protein-coupled receptor agonists and phorbol ester. Activation of the extracellular signal-regulated kinase cascade by phorbol ester is mediated by ras. The Journal of biological chemistry.1999;274:19762-19770.
14. Thorburn A, Thorburn J, Chen SY, Powers S, Shubeita HE, Feramisco JR, Chien KR. Hras-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy. The Journal of biological chemistry. 1993;268:2244-2249.
15. Abdellatif M, Schneider MD. An effector-like function of ras gtpase-activating protein predominates in cardiac muscle cells. The Journal of biological chemistry. 1997;272:525-533.
16. Fuller SJ, Finn SG, Downward J, Sugden PH. Stimulation of gene expression in neonatal rat ventricular myocytes by ras is mediated by ral guanine nucleotide dissociation stimulator (ral.Gds) and phosphatidylinositol 3-kinase in addition to raf. The Biochemical journal.1998;335 (Pt 2):241-246.
17. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight gtpase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of rho kinase. The Journal of biological chemistry.1998;273:7725-7730.
18. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of ras and rho pathways. The Journal of biological chemistry.1996;271:31185-31190.
19. Thorburn J, Xu S, Thorburn A. Map kinase- and rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. The EMBO journal.1997; 16:1888-1900.
20. Aoki H, Izumo S, Sadoshima J. Angiotensin ii activates rhoa in cardiac myocytes: A critical role of rhoa in angiotensin ii-induced premyofibril formation. Circulation research.1998;82:666-676.
21. Hines WA, Thorburn A. Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytes. Journal of molecular and cellular cardiology.1998;30:485-494.
22. Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of the rhoa/rho kinase pathway. FEBS letters.2009;583:2997-3003.
23. Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. The Journal of cell biology.1997;139:115-127.
24. Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira, II, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldshmidt-Clermont PJ, Irani K, Finkel T. A requirement for the racl gtpase in the signal transduction pathway leading to cardiac myocyte hypertrophy. The Journal of clinical investigation. 1998;102:929-937.
25. Izumo S, Shioi T. Cardiac transgenic and gene-targeted mice as models of cardiac hypertrophy and failure:A problem of (new) riches. Journal of cardiac failure. 1998;4:263-270.
26. Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a mlc-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. The Journal of biological chemistry. 1995;270:23173-23178.
27. Zheng M, Dilly K, Dos Santos Cruz J, Li M, Gu Y, Ursitti JA, Chen J, Ross J, Jr., Chien KR, Lederer JW, Wang Y. Sarcoplasmic reticulum calcium defect in ras-induced hypertrophic cardiomyopathy heart. American journal of physiology. Heart and circulatory physiology.2004;286:H424-433.
28. Kai H, Muraishi A, Sugiu Y, Nishi H, Seki Y, Kuwahara F, Kimura A, Kato H, Imaizumi T. Expression of proto-oncogenes and gene mutation of sarcomeric proteins in patients with hypertrophic cardiomyopathy. Circulation research. 1998;83:594-601.
29. Ruan H, Mitchell S, Vainoriene M, Lou Q, Xie LH, Ren S, Goldhaber JI, Wang Y. Gi alpha 1-mediated cardiac electrophysiological remodeling and arrhythmia in hypertrophic cardiomyopathy. Circulation.2007;116:596-605.
30. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW,2nd, Ross J, Jr., Chien KR, Brown JH. Cardiac-specific overexpression of rhoa results in sinus and atrioventricular nodal dysfunction and contractile failure. The Journal of clinical investigation.1999; 103:1627-1634.
31. Cachero TG, Morielli AD, Peralta EG The small gtp-binding protein rhoa regulates a delayed rectifier potassium channel. Cell.1998;93:1077-1085.
32. Yatani A, Irie K, Otani T, Abdellatif M, Wei L. Rhoa gtpase regulates 1-type ca2+ currents in cardiac myocytes. American journal of physiology. Heart and circulatory physiology.2005;288:H650-659.
33. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation.2001;104:317-324.
34. Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in rockl+/-haploinsufficient mice. Circulation.2005; 112:2959-2965.
35. Wei L, Imanaka-Yoshida K, Wang L, Zhan S, Schneider MD, DeMayo FJ, Schwartz RJ. Inhibition of rho family gtpases by rho gdp dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation. Development.2002;129:1705-1714.
36. Wei L, Taffet GE, Khoury DS, Bo J, Li Y, Yatani A, Delaughter MC, Klevitsky R, Hewett TE, Robbins J, Michael LH, Schneider MD, Entman ML, Schwartz RJ. Disruption of rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved. FASEB journal:official publication of the Federation of American Societies for Experimental Biology. 2004;18:857-859.
37. Satoh M, Ogita H, Takeshita K, Mukai Y, Kwiatkowski DJ, Liao JK. Requirement of racl in the development of cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America.2006; 103:7432-7437.
38. Lu H, Fedak PW, Dai X, Du C, Zhou YQ, Henkelman M, Mongroo PS, Lau A, Yamabi H, Hinek A, Husain M, Hannigan G, Coles JG. Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. Circulation.2006; 114:2271-2279.
39. Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E, Yager K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. The Journal of clinical investigation. 2000;105:875-886.
40. Buscemi N, Murray C, Doherty-Kirby A, Lajoie G, Sussman MA, Van Eyk JE. Myocardial subproteomic analysis of a constitutively active racl-expressing transgenic mouse with lethal myocardial hypertrophy. American journal of physiology. Heart and circulatory physiology.2005;289:H2325-2333.
41. Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G Impact of hmg coa reductase inhibition on small gtpases in the heart. Cardiovascular research. 2002;53:911-920.
42. Ramirez MT, Sah VP, Zhao XL, Hunter JJ, Chien KR, Brown JH. The mekk-jnk pathway is stimulated by alphal-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy. The Journal of biological chemistry.1997;272:14057-14061.
43. Muslin AJ. Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. Trends in cardiovascular medicine.2005; 15:225-229.
44. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, Sugden PH. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. Journal of cellular physiology. 2007;212:311-322.
45. Proud CG. Ras, pi3-kinase and mtor signaling in cardiac hypertrophy. Cardiovascular research.2004;63:403-413.
46. Morissette MR, Sah VP, Glembotski CC, Brown JH. The rho effector, pkn, regulates anf gene transcription in cardiomyocytes through a serum response element. American journal of physiology. Heart and circulatory physiology. 2000;278:H1769-1774.
47. Satoh S, Ueda Y, Koyanagi M, Kadokami T, Sugano M, Yoshikawa Y, Makino N. Chronic inhibition of rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. Journal of molecular and cellular cardiology.2003;35:59-70.
48. Clerk A, Pham FH, Fuller SJ, Sahai E, Aktories K, Marais R, Marshall C, Sugden PH. Regulation of mitogen-activated protein kinases in cardiac myocytes through the small g protein rac1. Molecular and cellular biology.2001;21:1173-1184.
49. Kawamura S, Miyamoto S, Brown JH. Initiation and transduction of stretch-induced rhoa and racl activation through caveolae:Cytoskeletal regulation of erk translocation. The Journal of biological chemistry.2003;278:31111-31117.
50. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circulation research.2006;98:322-334.
51. Kuwahara K, Saito Y, Nakagawa O, Kishimoto I, Harada M, Ogawa E, Miyamoto Y, Hamanaka I, Kajiyama N, Takahashi N, Izumi T, Kawakami R, Tamura N, Ogawa Y, Nakao K. The effects of the selective rock inhibitor, y27632, on et-1-induced hypertrophic response in neonatal rat cardiac myocytes--possible involvement of rho/rock pathway in cardiac muscle cell hypertrophy. FEBS letters. 1999;452:314-318.
52. Yanazume T, Hasegawa K, Wada H, Morimoto T, Abe M, Kawamura T, Sasayama S. Rho/rock pathway contributes to the activation of extracellular signal-regulated kinase/gata-4 during myocardial cell hypertrophy. The Journal of biological chemistry.2002;277:8618-8625.
53. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K, Takeshita A. Long-term treatment with a specific rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circulation research.2004;94:46-52.
54. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A. Long-term inhibition of rho-kinase suppresses angiotensin ii-induced cardiovascular hypertrophy in rats in vivo:Effect on endothelial nad(p)h oxidase system. Circulation research.2003;93:767-775.
55. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. The Journal of clinical investigation.2001;108:1429-1437.
56. Higuchi Y, Otsu K, Nishida K, Hirotani S, Nakayama H, Yamaguchi O, Hikoso S, Kashiwase K, Takeda T, Watanabe T, Mano T, Matsumura Y, Ueno H, Hori M. The small gtp-binding protein rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear factor-kappa b. The Journal of biological chemistry.2003;278:20770-20777.
57. Maillet M, Lynch JM, Sanna B, York AJ, Zheng Y, Molkentin JD. Cdc42 is an antihypertrophic molecular switch in the mouse heart. The Journal of clinical investigation.2009; 119:3079-3088.
58. Li JM, Gall NP, Grieve DJ, Chen M, Shah AM. Activation of nadph oxidase during progression of cardiac hypertrophy to failure. Hypertension. 2002;40:477-484.
59. MacCarthy PA, Grieve DJ, Li JM, Dunster C, Kelly FJ, Shah AM. Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy:Role of reactive oxygen species and nadph oxidase. Circulation.2001;104:2967-2974.
60. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of a gp91(phox)-containing nadph oxidase in angiotensin ii-induced cardiac hypertrophy in mice. Circulation.2002; 105:293-296.
61. Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB. Role of reactive oxygen species and nad(p)h oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. American journal of physiology. Cell physiology. 2002;282:C926-934.
62. Odley A, Hahn HS, Lynch RA, Marreez Y, Osinska H, Robbins J, Dorn GW,2nd. Regulation of cardiac contractility by rab4-modulated beta2-adrenergic receptor recycling. Proceedings of the National Academy of Sciences of the United States of America.2004; 101:7082-7087.
63. Filipeanu CM, Zhou F, Lam ML, Kerut KE, Claycomb WC, Wu G. Enhancement of the recycling and activation of beta-adrenergic receptor by rab4 gtpase in cardiac myocytes. The Journal of biological chemistry.2006;281:11097-11103.
64. Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M, Adachi T, Ogawa S, Fukuda K. Dominant negative suppression of rad leads to qt prolongation and causes ventricular arrhythmias via modulation of 1-type ca2+ channels in the heart. Circulation research.2007; 101:69-77.
65. Chang L, Zhang J, Tseng YH, Xie CQ, Ilany J, Bruning JC, Sun Z, Zhu X, Cui T, Youker KA, Yang Q, Day SM, Kahn CR, Chen YE. Rad gtpase deficiency leads to cardiac hypertrophy. Circulation.2007; 116:2976-2983.