橙皮素对小鼠压力负荷诱导的心脏重构的保护作用及机制
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摘要
背景：心脏重构是心脏衰竭的关键环节,常继发于高血压等疾病引起的长期心脏负荷过重,心脏重构在初始阶段具有代偿功能,但心脏重构后期的心肌纤维化等会引起心脏功能障碍,它的特点是心脏肥大、纤维化、氧化应激和心肌细胞凋亡。目前已有报道Akt、PKC等多种信号通路参与了心脏重构各个过程,临床上有多种药物治疗心衰过程中的心脏重构,这些药物针对于心脏重构各环节。橙皮素,它属于柑橘类黄酮,主要包含黄酮类化合物,具有抗炎、抗肿瘤等多种药理性能。研究表明橙皮素具有一定的抗氧化和抗凋亡的功能,然而,橙皮素在心脏重构中的作用尚无报道,因此我们采用主动脉缩窄术(Aortic binding, AB)研究橙皮素对心脏重构过程中心肌肥大,纤维化、氧化应激和心肌细胞凋亡的影响。
实验方法：将野生型C57BL/6小鼠(雄性8～10周龄)随机分为对照-假手术组,橙皮素-假手术组,对照-手术组和橙皮素-手术组,采用主动脉缩窄术建立实验动物模型,手术成功后根据分组给予不同处理7周。主要通过以下指标检测心脏重构各过程和相关分子机制情况：
一、心肌肥厚：
1.采用心动超声仪检测不同组小鼠的心率和IVSd、LVDd、LVPWd、IVSs、 LVDs、LVPWs;
2.采用血流动力学监测各组小鼠LVEF、LVFS、ESP和dP/dT max;
3.采用解剖研究各组小鼠心脏重量(HW)、肺脏重量(LW)、心脏体重比(HW/BW)和心脏重量肋骨直径比(HW/TL);
4.采用组织切片WGA染色和HE染色研究各组小鼠心脏体积和心肌细胞横截面积；
5.采用实时定量PCR研究ANP、BNP、α-肌球蛋白重链(a-MHC)等增生性标记物的表达情况；
6.采用western blot研究各组小鼠心脏中PKC-Akt和MAPK信号通路信号分子的表达情况；
二、心肌纤维化：
1.采用PSR染色研究各组小鼠心肌纤维化情况；
2.采用实时定量PCR检测小鼠心肌纤维化介质的表达情况
2.采用western blot研究Smad蛋白级联相关蛋白的表达情况；
三、氧化应激
采用实时定量PCR检测小鼠心肌氧化酶亚基mRNA的表达情况；
四、细胞凋亡
1.采用TUNEL法检测各组小鼠心肌细胞凋亡情况
2.采用western blot研究Smad蛋白级联和裂解PARP、BAX、BCL-2等凋亡相关蛋白的表达情况。
实验结果：
第一部分：心肌肥厚
1.主动脉缩窄术引起小鼠的心率明显增加,假手术组心率为518士13.34beats/min,而AB小鼠心率增加到522.38±11.90beats/min,橙皮素处理组与假手术组无显著性差别；
2.AB术后LVEF、LVFS显著降低,
3.HE切片显示AB术后小鼠心脏体积和心肌细胞横截面积增大,而橙皮素能明显降低AB术引起的心脏体积和心肌细胞横截面积的增大；
4.实时定量PCR发现AB术后ANP等心肌增生标记物mRNA表达显著增加,橙皮素能显著降低这些心肌增生标记物；
5. western blot结果表明慢性压力负荷引起小鼠心肌PKCα/βⅡ-AKT和JNK信号通路的激活,橙皮素能降低这两个信号通路的激活.
第二部分：心肌纤维化
1.PSR染色结果表明AB术诱导的压力负荷引起左心室纤维化区域增大,胶原体积和含量增加,橙皮素明显降低这种现象；
2.实时定量PCR结果显示慢性压力负荷引起心肌组织中的TGF-β1等纤维化介质mRNA表达增加,橙皮素能显著降低这些纤维化介质的表达；
3. western blot结果表明压力负荷引起磷酸化的Smad2和Smad3表达显著增加,而与AB手术组相比,橙皮素显著降低Smad2和Smad3蛋白磷酸化水平。
第三部分：
一、氧化应激
实时定量PCR结果显示慢性压力负荷增加NADPH氧化酶亚单位mRNA表达,降低SODl和SOD2mRNA的表达,而橙皮素能降低NADPH氧化酶亚单位mRNA的表达、增加SOD1和SOD2mRNA的表达。
二、细胞凋亡
1.TUNEL法结果表明慢性压力负荷引起心肌细胞凋亡增加,橙皮素能减低心肌细胞的凋亡；
2. western blot实验显示慢性超压力负荷明显增加裂解PARP、BAX、BCL-2、 BCL-XL、Bak和裂解的caspase-3蛋白表达,橙皮素能抑制裂解PARP、Bax/Bcl-2、Bak和裂解的caspase-3等蛋白的表达。
结论：
1.主动脉缩窄术所致的慢性压力负荷引起小鼠心肌肥厚、心肌纤维化、氧化应激增加和心肌细胞凋亡；
2.橙皮素降低慢性压力负荷引起的心肌肥厚,该作用是通过PKCα/βⅡ-AKT和JNK信号通路实现的；
3.橙皮素通过Smad级联蛋白信号通路降低慢性压力负荷引起的心肌纤维化；
4.橙皮素降低压力负荷引起的心肌氧化应激；
5.橙皮素降低心肌细胞凋亡,并降低凋亡相关蛋白的表达；
这些结果表明,橙皮素是心脏重构和心脏衰竭的潜在治疗药物。
Background:Cardiac remodeling, which is caused by long-term cardiac overload caused by hypertension and other diseases, is a key factor of heart failure. In the initial stages, cardiac remodeling has compensatory function, but myocardial fibrosis may lead to cardiac dysfunction, which is characterized by cardiac hypertrophy, fibrosis, oxidative stress and apoptosis of myocardial cells. It has been reported that Akt, PKC and other signaling pathways were involved in various processes of cardiac remodeling. There are a variety of drugs in clinical treatment of heart failure in the processes of cardiac remodeling. Hesperetin, which belongs to citrus flavonoids, is mainly expressed in flavonoids. It has several pharmacological properties, such as anti-inflammatory, anti-tumor and so on. Hesperetin have some antioxidant and anti-apoptotic function, however, the role of hesperetin in cardiac remodeling remains elusive. So we study the effect of hesperetin on the process of cardiac remodeling, including myocardial hypertrophy, fibrosis, oxidative stress and cardiac myocyte apoptosis, by aortic banding (AB).
Methods: Wild-type C57BL/6mice (8-10weeks old male) were randomly were randomly assigned to four groups: vehicle-sham (n=10), hesperetin-sham (n=9), vehicle-AB (n=10) and hesperetin-AB (n=10). Aortic banding (AB) was performed as described previously. Then,1week after AB or surgery, the animals were treated with30mg/kg/day of hesperetin or vehicle for7weeks. We mainly study cardiac remodeling process and molecular mechanisms underlying the case through the following indicators:
A. cardiac hypertrophy:
1. detected different groups of mice heart rate and IVSd, LVDd, LVPWd, IVSs, LVDs, LVPWs by echocardiography;
2. monitored mice in each group LVEF, LVFS, ESP and dP/dT max by hemodynamic apparatus;
3. investigated mice heart weight (HW), lung weight (LW), heart weight ratio (HW/BW) and heart weight rib diameter ratio (HW/TL) by anatomical studies;
4. studied cardiac volume and cardiac myocyte cross-sectional area by using WGA staining and HE staining;
5. studied mRNA expression of ANP, BNP, a-myosin heavy chain (a-MHC) and other proliferative marker by using real-time quantitative PCR
6. investigated the protein expression of mice heart PKC-Akt and MAPK signaling pathways signaling molecules by western blot studies
B. myocardial fibrosis:
1. studied myocardial fibrosis mice in each group situations using PSR staining;
2. detected the expression of cardiac fibrosis media by real-time quantitative PCR
3. detected expression of Smad proteins cascade related protein using western blot
C. Oxidative Stress
Detected mRNA expression mouse myocardium oxidase subunit by real-time quantitative PCR
D. Apoptosis
1.detected myocyte apoptosis using TUNEL assay
2.detected the expression of Smad proteins cascade and cleavaged PARP, BAX, BCL-2and other apoptosis-related protein by western blot;
Results:
Part I:cardiac hypertrophy
1. Aorta banding significantly increased heart rate. The heart rate of vehicle-sham group is518±13.34, while heart rate increased to522.38±11.90in vehicle-AB group. There is no significant difference between hesperetin-AB group and vehicle-sham group;
2. LVEF, LVFS significantly reduced in vehicle-AB mice;
3. HE sections showed that heart volume and cross-sectional area of myocardial cells increased in vehicle-AB group, and hespertin can significantly reduce increasement of the volume and cardiac myocyte cross-sectional area, which is caused by AB surgery;
4. Real-time quantitative PCR indicated that myocardial proliferation markers,such as ANP mRNA, was significantly increased after AB surgery, hesperetin can significantly reduce cardiac markers proliferation;
5. Western blot results showed that in mice with chronic pressure overload induced the activation of myocardial PKCa/β Ⅱ-AKT and JNK signaling pathway, and hesperetin can reduce the activation of these two signaling pathways.
Part II:Myocardial fibrosis
1. PSR staining showed that AB surgery-induced left ventricular pressure overload increased areas of fibrosis, collagen volume and content. Hesperetin significantly reduce this phenomenon;
2. Real-time quantitative PCR results showed that chronic pressure overload increased mRNA expression of myocardial tissue fibrosis media such as TGF-β1. Hespertin can significantly reduce the expression of these fibrosis medium;
3. Western blot results showed that pressure overload significantly increased phosphorylation of Smad2and Smad3expression. While compared with the AB, hesperetin significantly reduced phosphorylation levels of Smad2and Smad3.
Part III:
First,Oxidative stress
Real-time quantitative PCR results showed that chronic pressure overload increased mRNA expression of NADPH oxidase subunit, reduced mRNA expression of SOD1and SOD2, whereas hesperetin can reduce the mRNA expression of NADPH oxidase subunit increased mRNA expression of SOD1and SOD2.
Second, Apoptosis
1. TUNEL results showed that chronic pressure overload increased myocardial apoptosis and hespertin can reduce cardiac myocyte apoptosis;
2. Western blot experiments showed that chronic pressure overload significant increased protein expression of cleavaged PARP, BAX, BCL-2, BCL-XL, Bak and cleaved caspase-3, and hesperetin can inhibit the protein expression of cleavaged PARP, Bax/Bcl-2, Bak and cleaved caspase-3, etc.
Conclusions:We found that orange flavonoid hesperetin protected against cardiac hypertrophy, fibrosis, apoptosis and dysfunction induced by aortic banding. These findings possible exploit a potential therapeutic drug to cardiac remodeling and heart failure.
实验方法：将野生型C57BL/6小鼠(雄性8～10周龄)随机分为对照-假手术组,橙皮素-假手术组,对照-手术组和橙皮素-手术组,采用主动脉缩窄术建立实验动物模型,手术成功后根据分组给予不同处理7周。主要通过以下指标检测心脏重构各过程和相关分子机制情况：
一、心肌肥厚：
1.采用心动超声仪检测不同组小鼠的心率和IVSd、LVDd、LVPWd、IVSs、 LVDs、LVPWs;
2.采用血流动力学监测各组小鼠LVEF、LVFS、ESP和dP/dT max;
3.采用解剖研究各组小鼠心脏重量(HW)、肺脏重量(LW)、心脏体重比(HW/BW)和心脏重量肋骨直径比(HW/TL);
4.采用组织切片WGA染色和HE染色研究各组小鼠心脏体积和心肌细胞横截面积；
5.采用实时定量PCR研究ANP、BNP、α-肌球蛋白重链(a-MHC)等增生性标记物的表达情况；
6.采用western blot研究各组小鼠心脏中PKC-Akt和MAPK信号通路信号分子的表达情况；
二、心肌纤维化：
1.采用PSR染色研究各组小鼠心肌纤维化情况；
2.采用实时定量PCR检测小鼠心肌纤维化介质的表达情况
2.采用western blot研究Smad蛋白级联相关蛋白的表达情况；
三、氧化应激
采用实时定量PCR检测小鼠心肌氧化酶亚基mRNA的表达情况；
四、细胞凋亡
1.采用TUNEL法检测各组小鼠心肌细胞凋亡情况
2.采用western blot研究Smad蛋白级联和裂解PARP、BAX、BCL-2等凋亡相关蛋白的表达情况。
实验结果：
第一部分：心肌肥厚
1.主动脉缩窄术引起小鼠的心率明显增加,假手术组心率为518士13.34beats/min,而AB小鼠心率增加到522.38±11.90beats/min,橙皮素处理组与假手术组无显著性差别；
2.AB术后LVEF、LVFS显著降低,
3.HE切片显示AB术后小鼠心脏体积和心肌细胞横截面积增大,而橙皮素能明显降低AB术引起的心脏体积和心肌细胞横截面积的增大；
4.实时定量PCR发现AB术后ANP等心肌增生标记物mRNA表达显著增加,橙皮素能显著降低这些心肌增生标记物；
5. western blot结果表明慢性压力负荷引起小鼠心肌PKCα/βⅡ-AKT和JNK信号通路的激活,橙皮素能降低这两个信号通路的激活.
第二部分：心肌纤维化
1.PSR染色结果表明AB术诱导的压力负荷引起左心室纤维化区域增大,胶原体积和含量增加,橙皮素明显降低这种现象；
2.实时定量PCR结果显示慢性压力负荷引起心肌组织中的TGF-β1等纤维化介质mRNA表达增加,橙皮素能显著降低这些纤维化介质的表达；
3. western blot结果表明压力负荷引起磷酸化的Smad2和Smad3表达显著增加,而与AB手术组相比,橙皮素显著降低Smad2和Smad3蛋白磷酸化水平。
第三部分：
一、氧化应激
实时定量PCR结果显示慢性压力负荷增加NADPH氧化酶亚单位mRNA表达,降低SODl和SOD2mRNA的表达,而橙皮素能降低NADPH氧化酶亚单位mRNA的表达、增加SOD1和SOD2mRNA的表达。
二、细胞凋亡
1.TUNEL法结果表明慢性压力负荷引起心肌细胞凋亡增加,橙皮素能减低心肌细胞的凋亡；
2. western blot实验显示慢性超压力负荷明显增加裂解PARP、BAX、BCL-2、 BCL-XL、Bak和裂解的caspase-3蛋白表达,橙皮素能抑制裂解PARP、Bax/Bcl-2、Bak和裂解的caspase-3等蛋白的表达。
结论：
1.主动脉缩窄术所致的慢性压力负荷引起小鼠心肌肥厚、心肌纤维化、氧化应激增加和心肌细胞凋亡；
2.橙皮素降低慢性压力负荷引起的心肌肥厚,该作用是通过PKCα/βⅡ-AKT和JNK信号通路实现的；
3.橙皮素通过Smad级联蛋白信号通路降低慢性压力负荷引起的心肌纤维化；
4.橙皮素降低压力负荷引起的心肌氧化应激；
5.橙皮素降低心肌细胞凋亡,并降低凋亡相关蛋白的表达；
这些结果表明,橙皮素是心脏重构和心脏衰竭的潜在治疗药物。
Background:Cardiac remodeling, which is caused by long-term cardiac overload caused by hypertension and other diseases, is a key factor of heart failure. In the initial stages, cardiac remodeling has compensatory function, but myocardial fibrosis may lead to cardiac dysfunction, which is characterized by cardiac hypertrophy, fibrosis, oxidative stress and apoptosis of myocardial cells. It has been reported that Akt, PKC and other signaling pathways were involved in various processes of cardiac remodeling. There are a variety of drugs in clinical treatment of heart failure in the processes of cardiac remodeling. Hesperetin, which belongs to citrus flavonoids, is mainly expressed in flavonoids. It has several pharmacological properties, such as anti-inflammatory, anti-tumor and so on. Hesperetin have some antioxidant and anti-apoptotic function, however, the role of hesperetin in cardiac remodeling remains elusive. So we study the effect of hesperetin on the process of cardiac remodeling, including myocardial hypertrophy, fibrosis, oxidative stress and cardiac myocyte apoptosis, by aortic banding (AB).
Methods: Wild-type C57BL/6mice (8-10weeks old male) were randomly were randomly assigned to four groups: vehicle-sham (n=10), hesperetin-sham (n=9), vehicle-AB (n=10) and hesperetin-AB (n=10). Aortic banding (AB) was performed as described previously. Then,1week after AB or surgery, the animals were treated with30mg/kg/day of hesperetin or vehicle for7weeks. We mainly study cardiac remodeling process and molecular mechanisms underlying the case through the following indicators:
A. cardiac hypertrophy:
1. detected different groups of mice heart rate and IVSd, LVDd, LVPWd, IVSs, LVDs, LVPWs by echocardiography;
2. monitored mice in each group LVEF, LVFS, ESP and dP/dT max by hemodynamic apparatus;
3. investigated mice heart weight (HW), lung weight (LW), heart weight ratio (HW/BW) and heart weight rib diameter ratio (HW/TL) by anatomical studies;
4. studied cardiac volume and cardiac myocyte cross-sectional area by using WGA staining and HE staining;
5. studied mRNA expression of ANP, BNP, a-myosin heavy chain (a-MHC) and other proliferative marker by using real-time quantitative PCR
6. investigated the protein expression of mice heart PKC-Akt and MAPK signaling pathways signaling molecules by western blot studies
B. myocardial fibrosis:
1. studied myocardial fibrosis mice in each group situations using PSR staining;
2. detected the expression of cardiac fibrosis media by real-time quantitative PCR
3. detected expression of Smad proteins cascade related protein using western blot
C. Oxidative Stress
Detected mRNA expression mouse myocardium oxidase subunit by real-time quantitative PCR
D. Apoptosis
1.detected myocyte apoptosis using TUNEL assay
2.detected the expression of Smad proteins cascade and cleavaged PARP, BAX, BCL-2and other apoptosis-related protein by western blot;
Results:
Part I:cardiac hypertrophy
1. Aorta banding significantly increased heart rate. The heart rate of vehicle-sham group is518±13.34, while heart rate increased to522.38±11.90in vehicle-AB group. There is no significant difference between hesperetin-AB group and vehicle-sham group;
2. LVEF, LVFS significantly reduced in vehicle-AB mice;
3. HE sections showed that heart volume and cross-sectional area of myocardial cells increased in vehicle-AB group, and hespertin can significantly reduce increasement of the volume and cardiac myocyte cross-sectional area, which is caused by AB surgery;
4. Real-time quantitative PCR indicated that myocardial proliferation markers,such as ANP mRNA, was significantly increased after AB surgery, hesperetin can significantly reduce cardiac markers proliferation;
5. Western blot results showed that in mice with chronic pressure overload induced the activation of myocardial PKCa/β Ⅱ-AKT and JNK signaling pathway, and hesperetin can reduce the activation of these two signaling pathways.
Part II:Myocardial fibrosis
1. PSR staining showed that AB surgery-induced left ventricular pressure overload increased areas of fibrosis, collagen volume and content. Hesperetin significantly reduce this phenomenon;
2. Real-time quantitative PCR results showed that chronic pressure overload increased mRNA expression of myocardial tissue fibrosis media such as TGF-β1. Hespertin can significantly reduce the expression of these fibrosis medium;
3. Western blot results showed that pressure overload significantly increased phosphorylation of Smad2and Smad3expression. While compared with the AB, hesperetin significantly reduced phosphorylation levels of Smad2and Smad3.
Part III:
First,Oxidative stress
Real-time quantitative PCR results showed that chronic pressure overload increased mRNA expression of NADPH oxidase subunit, reduced mRNA expression of SOD1and SOD2, whereas hesperetin can reduce the mRNA expression of NADPH oxidase subunit increased mRNA expression of SOD1and SOD2.
Second, Apoptosis
1. TUNEL results showed that chronic pressure overload increased myocardial apoptosis and hespertin can reduce cardiac myocyte apoptosis;
2. Western blot experiments showed that chronic pressure overload significant increased protein expression of cleavaged PARP, BAX, BCL-2, BCL-XL, Bak and cleaved caspase-3, and hesperetin can inhibit the protein expression of cleavaged PARP, Bax/Bcl-2, Bak and cleaved caspase-3, etc.
Conclusions:We found that orange flavonoid hesperetin protected against cardiac hypertrophy, fibrosis, apoptosis and dysfunction induced by aortic banding. These findings possible exploit a potential therapeutic drug to cardiac remodeling and heart failure.
引文
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[6].Talan MI, Ahmet I, Xiao RP, Lakatta EG:Beta2 AR agonists in treatment of chronic heart failure:long path to translation. J Mol Cell Cardiol 2011,51:529-533.
[7].Messaoudi S, Azibani F, Delcayre C, Jaisser F:Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012,350:266-272.
[8].Yin WH, Chen YH, Wei J, Jen HL, Huang WP, Young MS, Chen DC, Liu PL:Associations between endothelin-1 and adiponectin in chronic heart failure. Cardiology 2011,118:207-216.
[9].Distefano G: Rimodellamento miocardico e nuove strategie terapeutiche nella insufficienza cardiaca cronica. Riv Ital Pediatr 2001,27:311-317.
[10].Shah AM, Mann DL:In search of new therapeutic targets and strategies for heart failure:recent advances in basic science. Lancet 2011,78:704-712.
[11].Palomeque J, Delbridge L, Petroff MV: Angiotensin II: a regulator of cardiomyocyte function and survival. Frontiers in Bioscience 2009,14:5118-5133.
[12].Antos CL, McKinsey TA, Frey N et al (2002) Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 99:907-912.
[13].McMullen JR, Sherwood MC, Tarnavski O et al (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050-3055.
[14].Skurk C, Izumiya Y, Maatz H et al (2005) The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem 280:20814-20823.
[15].DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ (2006) Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281:32841-32851.
[16].Ni YG, Berenji K, Wang N et al (2006) Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation 114:1159-1168.
[17].Soesanto W, Lin HY, Hu E et al (2009) Mammalian target of rapamycin is a critical regulator of cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 54:1321-1327.
[18].Keranen LM, Dutil EM, Newton AC (1995) Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol 5:1394-1403.
[19].Sabri A, Steinberg SF (2003) Protein kinase C isoform-selective signals that lead to cardiac hypertrophy and the progression of heart failure. Mol Cell Biochem 251:97-101.
[20].Li HL, Wang AB, Huang Y et al (2005) Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways. Free Radic Biol Med 38:243-257.
[21].Yan L, Huang H, Tang QZ et al (2010) Breviscapine protects against cardiac hypertrophy through blocking PKC-alpha-dependent signaling. J Cell Biochem 109:1158-1171.
[22].Palfi A, Toth A, Hanto K et al (2006) PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway. J Mol Cell Cardiol 41:149-159.
[23].Bisping E, Ikeda S, Kong SW et al (2006) Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc Natl Acad Sci U S A 103:14471-14476.
[24].Fan X, Turdi S, Ford SP et al (2011) Influence of gestational overfeeding on cardiac morphometry and hypertrophic protein markers in fetal sheep. J Nutr Biochem 22:30-37.
[25].Kim JY, Jung KJ, Choi JS, Chung HY (2006) Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin. Aging Cell 5:401-411.
[26].Shih CH, Lin LH, Hsu HT et al (2012) Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia. Evid Based Complement Alternat Med 2012:472897.
[27].Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35:1385-1394.
[28].Wang N, Guan P, Zhang JP et al (2011) Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses isoproterenol-induced heart failure in rats via JNK and ERK1/2 pathways. J Cell Biochem 112:1920-1929.
[29].Fan GC, Yuan Q, Song G et al (2006) Small heat-shock protein Hsp20 attenuates beta-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1. Circ Res 99:1233-1242.
[30].Chaanine AH, Jeong D, Liang L et al (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265.
[31].Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568-575.
[32].Li P, Wang D, Lucas J et al (2008) Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102:185-192.
[33].Octavia Y, Brunner-La RHP, Moens AL (2012) NADPH oxidase-dependent oxidative stress in the failing heart: From pathogenic roles to therapeutic approach. Free Radic Biol Med 52:291-297.
[34].Burgoyne JR, Mongue-Din H, Eaton P, Shah AM (2012) Redox signaling in cardiac physiology and pathology. Circ Res 111:1091-1106.
[35].Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191-227.
[36].Singh SS, Kang PM (2011) Mechanisms and inhibitors of apoptosis in cardiovascular diseases. Curr Pharm Des 17:1783-1793.
[37].Wong WW, Puthalakath H (2008) Bcl-2 family proteins:the sentinels of the mitochondrial apoptosis pathway. IUBMB Life 60:390-397.
[1]Distefano G: Aspetti peculiari della terapia dello scompenso cardiaconell'infanzia. Revisione della letteratura e dati personali. Ped Med Chir 1991,13:333-344.
[2]Krum H, Abraham WT: Heart failure. Lancet 2009,373:941-955.
[3]Kozlik R, Kramer HH, Wicht H, Krian A, Ostermeyer J, Reinhardt D: Myocardial beta-adrenoceptor density and the distribution of beta 1-and beta 2-adrenoceptor subpopulations in children with congenital heart disease. Eur J Pediatr 1991,150:388-394.
[4]Weber KT: Aldosterone and spironolactone in heart failure. N Engl J Med 1999,341:753-754.
[5]B Swynghedauw (ed.):Molecular Cardiology for the Cardiologist. Second Edition: Kluwer Academic Publishers; 1998.
[6]Colucci WS: Molecular and cellular mechanism of myocardial failure.J Cardiol 1997,80: 15L-25L.
[7]Bristow MR: Why does the myocardium fail? Insights from basic science. Lancet 1998, 352:8-14.
[8]Soltysinsca E, Olesen SP, Osadchii OE:Myocardial structural, contractile and electrophy-siological changes in the guinea -pig heart failure model induced by chronic sympathetic activation. Exp Physiol 2011,96:647-663.
[9]Talan MI, Ahmet I, Xiao RP, Lakatta EG:Beta2 AR agonists in treatment of chronic heart failure:long path to translation. J Mol Cell Cardiol 2011,51:529-533.
[10]Messaoudi S, Azibani F, Delcayre C, Jaisser F:Aldosterone,mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012,350:266-272.
[11]Yin WH, Chen YH, Wei J, Jen HL, Huang WP, Young MS, Chen DC, Liu PL:Associations between endothelin-1 and adiponectin in chronic heart failure. Cardiology 2011,118:207-216.
[12]Distefano G: Rimodellamento miocardico e nuove strategie terapeutiche nella insufficienza cardiaca cronica. Riv Ital Pediatr 2001,27:311-317.
[13]Shah AM, Mann DL: In search of new therapeutic targets and strategies for heart failure:recent advances in basic science. Lancet 2011,378:704-712.
[14]Palomeque J, Delbridge L, Petroff MV: Angiotensin II:a regulator of cardiomyocyte function and survival. Frontiers in Bioscience 2009,14:5118-5133.
[15]Izumo S, Nadal-Ginard B, Mahdavi V: Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Nat Acad Sci USA 1998,85:339-343.
[16]Kuwahara K, Nakao K: New molecular mechanisms for cardiovascular disease:transcriptional pathways and novel therapeutic targets in heart filure. J Pharmacol Sci 2011,116:337-342.
[17]Dhalla NS, Saini-Chohan HK, Rodriguez-Leyva D, Elimban V, Dent MR, Tappia PS: Subcellular remodeling may induce cardiac dysfunction in congestive heart failure. Cardiovasc Res 2009,81:429-438.
[18]Diwan A, Dorn GW Ⅱ:Decompensation of cardiac hypertrophy:cellular mechanisms and novel therapeutic targets. Physiology 2007,22:56-64.
[19]Chien KR: Stress pathways and heart failure. Cell 1999,98:555-558.
[20]Weber KT, Brilla CG, Janicki JS:Myocardial fibrosis:its functional significance and regulatory factors. Cardiovasc Res 1993,27:341-348.
[21]Dorn GW Ⅱ:Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodeling. Cardiovasc Res 2009,81:465-473.
[22]Hunter JJ, Chien KR: Signaling pathways for cardiac hypertrophy and failure. New Engl J Med 1999,341:1276-1283.
[23]Bernardo BC, Weeks KL, Pretorius L, McMullen JR: Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacology and Therapeutics 2010,128:191-227.
[24]Givertz MM, Colucci WS:New target for heart failure therapy:endothelin, inflammatory cytochines and oxidative stress. Lancet 1998,352(Suppl 1):S134-S138.
[25]Eichorn EJ, Bistow MR: Practical guidelines for initiation of beta- adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997,79:794-798.
[26]Bristow MR, Gilbert EM, Lowes BD: Changes in myocardial gene expression associated with beta-blocker-related improvement in ventricular systolic function. Circulation 1997,96:1-92. Abstract.
[27]Kirkby NS, Hadoke PWF, Bagnall AJ, Webb DJ:The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Brit J Pharmacol 2008, 153:1105-1119.
[28]Bozkurt B, Mann DL, Deswal A: Biomarkers of inflammation in heart failure. Heart Fail Rev2010,15:331-341.
[29]Chung ES, Packer M, Lo KA, Fasanmade AA, Willerson JT: Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the Anti-TNF Therapy AgainstCongestive Heart Failure (ATTACH) trial. Circulation 2003,107:3133-3140.
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[32]McKinsey TA:Targeting inflammation in heart failure with Histone Deacetylase Inhibitors. Mol Med 2011,17(5-6):434-441.
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[2].Barry SP, Townsend PA (2010) What causes a broken heart--nolecular insights into heart failure. Int Rev Cell Mol Biol 284:113-179.
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[1]. Zong J, Deng W, Zhou H et al (2013) 3,3'-Diindolylmethane Protects against Cardiac Hypertrophy via 5'-Adenosine Monophosphate-Activated Protein Kinase-alpha2. PLOS ONE 8:e53427.
[2]. Deng W, Zong J, Bian Z et al (2013) Indole-3-carbinol protects against pressure overload induced cardiac remodeling via activating AMPK-alpha. LID-10.1002/mnfr.201300012 [doi]. Mol Nutr Food Res.
[3].Distefano G:Aspetti peculiari della terapia dello scompenso cardiaconell'infanzia. Revisione della letteratura e dati personali. Ped Med Chir 1991,13:333-344.
[4].Krum H, Abraham WT: Heart failure. Lancet 2009,373:941-955.
[5].Soltysinsca E, Olesen SP, Osadchii OE:Myocardial structural, contractile and electrophysiological changes in the guinea-pig heart failure model induced by chronic sympathetic activation. Exp Physiol 2011,96:647-663.
[6].Talan MI, Ahmet I, Xiao RP, Lakatta EG:Beta2 AR agonists in treatment of chronic heart failure:long path to translation. J Mol Cell Cardiol 2011,51:529-533.
[7].Messaoudi S, Azibani F, Delcayre C, Jaisser F:Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012,350:266-272.
[8].Yin WH, Chen YH, Wei J, Jen HL, Huang WP, Young MS, Chen DC, Liu PL:Associations between endothelin-1 and adiponectin in chronic heart failure. Cardiology 2011,118:207-216.
[9].Distefano G: Rimodellamento miocardico e nuove strategie terapeutiche nella insufficienza cardiaca cronica. Riv Ital Pediatr 2001,27:311-317.
[10].Shah AM, Mann DL:In search of new therapeutic targets and strategies for heart failure:recent advances in basic science. Lancet 2011,78:704-712.
[11].Palomeque J, Delbridge L, Petroff MV: Angiotensin II: a regulator of cardiomyocyte function and survival. Frontiers in Bioscience 2009,14:5118-5133.
[12].Antos CL, McKinsey TA, Frey N et al (2002) Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 99:907-912.
[13].McMullen JR, Sherwood MC, Tarnavski O et al (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050-3055.
[14].Skurk C, Izumiya Y, Maatz H et al (2005) The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem 280:20814-20823.
[15].DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ (2006) Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281:32841-32851.
[16].Ni YG, Berenji K, Wang N et al (2006) Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation 114:1159-1168.
[17].Soesanto W, Lin HY, Hu E et al (2009) Mammalian target of rapamycin is a critical regulator of cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 54:1321-1327.
[18].Keranen LM, Dutil EM, Newton AC (1995) Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol 5:1394-1403.
[19].Sabri A, Steinberg SF (2003) Protein kinase C isoform-selective signals that lead to cardiac hypertrophy and the progression of heart failure. Mol Cell Biochem 251:97-101.
[20].Li HL, Wang AB, Huang Y et al (2005) Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways. Free Radic Biol Med 38:243-257.
[21].Yan L, Huang H, Tang QZ et al (2010) Breviscapine protects against cardiac hypertrophy through blocking PKC-alpha-dependent signaling. J Cell Biochem 109:1158-1171.
[22].Palfi A, Toth A, Hanto K et al (2006) PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway. J Mol Cell Cardiol 41:149-159.
[23].Bisping E, Ikeda S, Kong SW et al (2006) Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc Natl Acad Sci U S A 103:14471-14476.
[24].Fan X, Turdi S, Ford SP et al (2011) Influence of gestational overfeeding on cardiac morphometry and hypertrophic protein markers in fetal sheep. J Nutr Biochem 22:30-37.
[25].Kim JY, Jung KJ, Choi JS, Chung HY (2006) Modulation of the age-related nuclear factor-kappaB (NF-kappaB) pathway by hesperetin. Aging Cell 5:401-411.
[26].Shih CH, Lin LH, Hsu HT et al (2012) Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia. Evid Based Complement Alternat Med 2012:472897.
[27].Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35:1385-1394.
[28].Wang N, Guan P, Zhang JP et al (2011) Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses isoproterenol-induced heart failure in rats via JNK and ERK1/2 pathways. J Cell Biochem 112:1920-1929.
[29].Fan GC, Yuan Q, Song G et al (2006) Small heat-shock protein Hsp20 attenuates beta-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1. Circ Res 99:1233-1242.
[30].Chaanine AH, Jeong D, Liang L et al (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265.
[31].Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568-575.
[32].Li P, Wang D, Lucas J et al (2008) Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102:185-192.
[33].Octavia Y, Brunner-La RHP, Moens AL (2012) NADPH oxidase-dependent oxidative stress in the failing heart: From pathogenic roles to therapeutic approach. Free Radic Biol Med 52:291-297.
[34].Burgoyne JR, Mongue-Din H, Eaton P, Shah AM (2012) Redox signaling in cardiac physiology and pathology. Circ Res 111:1091-1106.
[35].Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191-227.
[36].Singh SS, Kang PM (2011) Mechanisms and inhibitors of apoptosis in cardiovascular diseases. Curr Pharm Des 17:1783-1793.
[37].Wong WW, Puthalakath H (2008) Bcl-2 family proteins:the sentinels of the mitochondrial apoptosis pathway. IUBMB Life 60:390-397.
[1]Distefano G: Aspetti peculiari della terapia dello scompenso cardiaconell'infanzia. Revisione della letteratura e dati personali. Ped Med Chir 1991,13:333-344.
[2]Krum H, Abraham WT: Heart failure. Lancet 2009,373:941-955.
[3]Kozlik R, Kramer HH, Wicht H, Krian A, Ostermeyer J, Reinhardt D: Myocardial beta-adrenoceptor density and the distribution of beta 1-and beta 2-adrenoceptor subpopulations in children with congenital heart disease. Eur J Pediatr 1991,150:388-394.
[4]Weber KT: Aldosterone and spironolactone in heart failure. N Engl J Med 1999,341:753-754.
[5]B Swynghedauw (ed.):Molecular Cardiology for the Cardiologist. Second Edition: Kluwer Academic Publishers; 1998.
[6]Colucci WS: Molecular and cellular mechanism of myocardial failure.J Cardiol 1997,80: 15L-25L.
[7]Bristow MR: Why does the myocardium fail? Insights from basic science. Lancet 1998, 352:8-14.
[8]Soltysinsca E, Olesen SP, Osadchii OE:Myocardial structural, contractile and electrophy-siological changes in the guinea -pig heart failure model induced by chronic sympathetic activation. Exp Physiol 2011,96:647-663.
[9]Talan MI, Ahmet I, Xiao RP, Lakatta EG:Beta2 AR agonists in treatment of chronic heart failure:long path to translation. J Mol Cell Cardiol 2011,51:529-533.
[10]Messaoudi S, Azibani F, Delcayre C, Jaisser F:Aldosterone,mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012,350:266-272.
[11]Yin WH, Chen YH, Wei J, Jen HL, Huang WP, Young MS, Chen DC, Liu PL:Associations between endothelin-1 and adiponectin in chronic heart failure. Cardiology 2011,118:207-216.
[12]Distefano G: Rimodellamento miocardico e nuove strategie terapeutiche nella insufficienza cardiaca cronica. Riv Ital Pediatr 2001,27:311-317.
[13]Shah AM, Mann DL: In search of new therapeutic targets and strategies for heart failure:recent advances in basic science. Lancet 2011,378:704-712.
[14]Palomeque J, Delbridge L, Petroff MV: Angiotensin II:a regulator of cardiomyocyte function and survival. Frontiers in Bioscience 2009,14:5118-5133.
[15]Izumo S, Nadal-Ginard B, Mahdavi V: Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Nat Acad Sci USA 1998,85:339-343.
[16]Kuwahara K, Nakao K: New molecular mechanisms for cardiovascular disease:transcriptional pathways and novel therapeutic targets in heart filure. J Pharmacol Sci 2011,116:337-342.
[17]Dhalla NS, Saini-Chohan HK, Rodriguez-Leyva D, Elimban V, Dent MR, Tappia PS: Subcellular remodeling may induce cardiac dysfunction in congestive heart failure. Cardiovasc Res 2009,81:429-438.
[18]Diwan A, Dorn GW Ⅱ:Decompensation of cardiac hypertrophy:cellular mechanisms and novel therapeutic targets. Physiology 2007,22:56-64.
[19]Chien KR: Stress pathways and heart failure. Cell 1999,98:555-558.
[20]Weber KT, Brilla CG, Janicki JS:Myocardial fibrosis:its functional significance and regulatory factors. Cardiovasc Res 1993,27:341-348.
[21]Dorn GW Ⅱ:Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodeling. Cardiovasc Res 2009,81:465-473.
[22]Hunter JJ, Chien KR: Signaling pathways for cardiac hypertrophy and failure. New Engl J Med 1999,341:1276-1283.
[23]Bernardo BC, Weeks KL, Pretorius L, McMullen JR: Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacology and Therapeutics 2010,128:191-227.
[24]Givertz MM, Colucci WS:New target for heart failure therapy:endothelin, inflammatory cytochines and oxidative stress. Lancet 1998,352(Suppl 1):S134-S138.
[25]Eichorn EJ, Bistow MR: Practical guidelines for initiation of beta- adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997,79:794-798.
[26]Bristow MR, Gilbert EM, Lowes BD: Changes in myocardial gene expression associated with beta-blocker-related improvement in ventricular systolic function. Circulation 1997,96:1-92. Abstract.
[27]Kirkby NS, Hadoke PWF, Bagnall AJ, Webb DJ:The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Brit J Pharmacol 2008, 153:1105-1119.
[28]Bozkurt B, Mann DL, Deswal A: Biomarkers of inflammation in heart failure. Heart Fail Rev2010,15:331-341.
[29]Chung ES, Packer M, Lo KA, Fasanmade AA, Willerson JT: Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the Anti-TNF Therapy AgainstCongestive Heart Failure (ATTACH) trial. Circulation 2003,107:3133-3140.
[30]Mann DL, McMurray JJ, Packer M: Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004,109:1594-1602.
[31]Shaw ST, Shah MKH, Williams SG, Fildes JE: Immunological mechanisms of pentoxifylline in chronic heart failure. Eur J Heart Fail 2009,11:113-118.
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