不同剂量Rho激酶抑制剂对急性心肌梗死大鼠心肌细胞凋亡的影响
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摘要
目的:急性心肌梗死(acute myocardial infraction, AMI)后,出现心室重构,进而发展为心力衰竭(heart failure, HF),终因心力衰竭而导致死亡,目前HF尚无有效的治疗方法,故预防心室重构至关重要。近年来研究表明,心肌细胞凋亡也是心肌细胞的一种重要的死亡形式,在AMI后的心室重塑中起了很重要的作用。Rho激酶介导了一系列的细胞生物学行为,包括细胞凋亡。
本研究通过观察大鼠急性心肌梗死(acute myocardial infarction, AMI)后心肌梗死面积、心肌细胞凋亡及Bcl-2和Bax表达的情况,以评价不同剂量Rho激酶抑制剂(法舒地尔, Fasudil)对大鼠AMI后心肌的保护作用。
方法:健康雄性Sprague Dawley(SD)大鼠54只随机分为5组,假手术组(Sham):仅在左冠状动脉前降支(LAD)下穿线但不结扎;AMI组:结扎LAD;法舒地尔大剂量治疗组(High dose fasudil treated, HDFT):结扎LAD;法舒地尔中剂量治疗组(Intermediate dose fasudil treated, IDFT):结扎LAD;法舒地尔小剂量治疗组(Low dose fasudil treated, LDFT):结扎LAD。术前1h Sham组和AMI组分别给予生理盐水0.5ml腹腔注射,术前1h法舒地尔大剂量治疗组给予法舒地尔30mg/kg腹腔注射,法舒地尔中剂量治疗组给予法舒地尔10mg/kg腹腔注射,法舒地尔小剂量治疗组给予法舒地尔1mg/kg腹腔注射。术后24h,伊文蓝-红四氮唑双染色,确定缺血面积和梗死面积,TUNEL法检测缺血区凋亡细胞,免疫组织化学染色法检测缺血区Bcl-2和Bax的表达。
结果:
1心肌梗死面积的比较
与AMI组相比,HDF组与IDF组大鼠的心肌梗死面积均显著下降,且差别有统计学意义(P<0.01);LDF组大鼠的心肌梗死面积与AMI组相当,差别无统计学意义(P >0.05);IDF组较LDF组大鼠的心肌梗死面积显著下降,且差别有统计学意义(P<0.01)。
2 Bcl-2蛋白表达的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞Bcl-2蛋白的表达均显著降低,且差别有统计学意义(P <0.01);与AMI组相比,HDF组和IDF组Bcl-2蛋白的表达均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组Bcl-2蛋白的表达升高,但差别无统计学意义(P >0.05);HDF组和IDF组比较Bcl-2蛋白的表达显著升高,差别有统计学意义(P<0.01);IDF组和LDF组比较Bcl-2蛋白的表达显著升高,差别有统计学意义(P<0.01)。
3 Bax蛋白表达的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞Bax蛋白的表达均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组、IDF组及HDF组Bax蛋白的表达均显著降低,且差别有统计学意义(P<0.01);HDF组和IDF组比较Bax蛋白的表达显著降低,差别有统计学意义(P <0.01);IDF组和LDF组比较Bax蛋白的表达显著降低,差别有统计学意义(P <0.01)。
4心肌细胞凋亡的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞凋亡指数均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组、IDF组及HDF组心肌细胞凋亡指数均显著降低,且差别有统计学意义(P<0.01);HDF组和IDF组比较心肌细胞凋亡指数显著降低,差别有统计学意义(P <0.01);IDF组和LDF组比较心肌细胞凋亡指数显著降低,差别有统计学意义(P <0.01)。
结论:本研究对AMI后大鼠应用不同剂量法舒地尔干预,结果显示法舒地尔具有以下作用:1提高AMI后缺血区Bcl-2的表达。2降低AMI后缺血区Bax的表达。3减少AMI后缺血区细胞凋亡水平。4减低AMI后的心肌梗死面积。以上作用与剂量相关,大剂量的作用较强。
Objective: The ventricular remodeling after acute myocardial infarction (AMI), and then the heart failure (HF), eventually lead to death. Currently, there is no effective treatment to prevent it, so the prevention of ventricular remodeling is essential. Recent studies have shown that cardiomyocyte apoptosis is an imperative form of death and it play an important role in ventricular remodeling after acute myocardial infarction. Rho-kinase mediated a series of behavior of cell biology, including cell apoptosis.
In this study,myocardial infarction area,cardiomyocyte apoptosis and the expression of Bcl-2 and Bax were obtained after acute myocardial infarction(AMI) in rats,and to study the protection effects of different doses fasudil,a Rho-kinase inhibitor ,on the myocardium of rats with AMI.
Methods: Fifty-four healthy male SD rats were subjected to left anterior descending coronary artery(LAD) ligation and were divided randomly into five groups:Sham operation group(not ligation of LAD) ,AMI group, high dose fasudil treated(HDFT) group, intermediate dose fasudil treated(IDFT) group and Low dose fasudil treated (LDFT)group. 1h before surgery the rats received intraperitoneal injection normal saline 0.5ml ( sham group and AMI group) ,30mg/kg fasudil (HDFT group), 10mg/kg fasudil(IDFT group) and 1mg/kg fasudil(LDFT group). At 24 hours after coronary ligation,the rats were sacrificed.The myocardial infarction area and ischemia area were determined by evans-bule and TTC double staining.The cardiocyte apoptosis in the ischemia region was determined by TUNEL assay and the apoptotic index(AI) were calculated.The Bcl-2 and Bax protein expressions were measured by immunohistochemical staining.
Results: 1 Compared with the AMI group, the myocardial infarction area reduced obviously in HDF group and IDF group(P <0.01);There was not statistically significant between LDF group and AMI group(P >0.05);Compared with the LDF group, the myocardial infarction area reduced obviously in IDF group(P<0.01).
2 Compared with the Sham group, the expression of Bcl-2 reduced obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the expression of Bcl-2 increased obviously in HDF group and IDF group(P <0.01);There was not statistically significant between AMI group and LDF group(P >0.05);Compared with the IDF group, the expression of Bcl-2 increased obviously in HDF group(P<0.01). Compared with the LDF group, the expression of Bcl-2 increased obviously in LDF group(P<0.01).
3 Compared with the Sham group, the expression of Bax increased obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the expression of Bax reduced obviously in LDF group, IDF group and HDF group(P <0.01);Compared with the IDF group, the expression of Bax reduced obviously in HDF group(P<0.01). Compared with the LDF group, the expression of Bax reduced obviously in IDF group(P<0.01).
4 Compared with the Sham group, the cardiomyocyte apoptotic index increased obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the cardiomyocyte apoptotic index reduced obviously in LDF group, IDF group and HDF group(P <0.01);Compared with the IDF group, the cardiomyocyte apoptotic index reduced obviously in HDF group(P<0.01). Compared with the LDF group, the cardiomyocyte apoptotic index reduced obviously in IDF group(P<0.01).
Conclusion: Different Doses Fasudil intervention after AMI in rats can be illustnated as follows, (1) increase the expression of Bcl-2.(2) reduce the expression of Bax.(3) reduce the Cardiocyte apoptosis.(4) reduce the myocardial infarction area. These effects has dose-dependently, and the higer dose the better results.
本研究通过观察大鼠急性心肌梗死(acute myocardial infarction, AMI)后心肌梗死面积、心肌细胞凋亡及Bcl-2和Bax表达的情况,以评价不同剂量Rho激酶抑制剂(法舒地尔, Fasudil)对大鼠AMI后心肌的保护作用。
方法:健康雄性Sprague Dawley(SD)大鼠54只随机分为5组,假手术组(Sham):仅在左冠状动脉前降支(LAD)下穿线但不结扎;AMI组:结扎LAD;法舒地尔大剂量治疗组(High dose fasudil treated, HDFT):结扎LAD;法舒地尔中剂量治疗组(Intermediate dose fasudil treated, IDFT):结扎LAD;法舒地尔小剂量治疗组(Low dose fasudil treated, LDFT):结扎LAD。术前1h Sham组和AMI组分别给予生理盐水0.5ml腹腔注射,术前1h法舒地尔大剂量治疗组给予法舒地尔30mg/kg腹腔注射,法舒地尔中剂量治疗组给予法舒地尔10mg/kg腹腔注射,法舒地尔小剂量治疗组给予法舒地尔1mg/kg腹腔注射。术后24h,伊文蓝-红四氮唑双染色,确定缺血面积和梗死面积,TUNEL法检测缺血区凋亡细胞,免疫组织化学染色法检测缺血区Bcl-2和Bax的表达。
结果:
1心肌梗死面积的比较
与AMI组相比,HDF组与IDF组大鼠的心肌梗死面积均显著下降,且差别有统计学意义(P<0.01);LDF组大鼠的心肌梗死面积与AMI组相当,差别无统计学意义(P >0.05);IDF组较LDF组大鼠的心肌梗死面积显著下降,且差别有统计学意义(P<0.01)。
2 Bcl-2蛋白表达的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞Bcl-2蛋白的表达均显著降低,且差别有统计学意义(P <0.01);与AMI组相比,HDF组和IDF组Bcl-2蛋白的表达均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组Bcl-2蛋白的表达升高,但差别无统计学意义(P >0.05);HDF组和IDF组比较Bcl-2蛋白的表达显著升高,差别有统计学意义(P<0.01);IDF组和LDF组比较Bcl-2蛋白的表达显著升高,差别有统计学意义(P<0.01)。
3 Bax蛋白表达的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞Bax蛋白的表达均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组、IDF组及HDF组Bax蛋白的表达均显著降低,且差别有统计学意义(P<0.01);HDF组和IDF组比较Bax蛋白的表达显著降低,差别有统计学意义(P <0.01);IDF组和LDF组比较Bax蛋白的表达显著降低,差别有统计学意义(P <0.01)。
4心肌细胞凋亡的比较
与Sham组相比,AMI组、LDF组、IDF组及HDF组缺血区心肌细胞凋亡指数均显著升高,且差别有统计学意义(P <0.01);与AMI组相比,LDF组、IDF组及HDF组心肌细胞凋亡指数均显著降低,且差别有统计学意义(P<0.01);HDF组和IDF组比较心肌细胞凋亡指数显著降低,差别有统计学意义(P <0.01);IDF组和LDF组比较心肌细胞凋亡指数显著降低,差别有统计学意义(P <0.01)。
结论:本研究对AMI后大鼠应用不同剂量法舒地尔干预,结果显示法舒地尔具有以下作用:1提高AMI后缺血区Bcl-2的表达。2降低AMI后缺血区Bax的表达。3减少AMI后缺血区细胞凋亡水平。4减低AMI后的心肌梗死面积。以上作用与剂量相关,大剂量的作用较强。
Objective: The ventricular remodeling after acute myocardial infarction (AMI), and then the heart failure (HF), eventually lead to death. Currently, there is no effective treatment to prevent it, so the prevention of ventricular remodeling is essential. Recent studies have shown that cardiomyocyte apoptosis is an imperative form of death and it play an important role in ventricular remodeling after acute myocardial infarction. Rho-kinase mediated a series of behavior of cell biology, including cell apoptosis.
In this study,myocardial infarction area,cardiomyocyte apoptosis and the expression of Bcl-2 and Bax were obtained after acute myocardial infarction(AMI) in rats,and to study the protection effects of different doses fasudil,a Rho-kinase inhibitor ,on the myocardium of rats with AMI.
Methods: Fifty-four healthy male SD rats were subjected to left anterior descending coronary artery(LAD) ligation and were divided randomly into five groups:Sham operation group(not ligation of LAD) ,AMI group, high dose fasudil treated(HDFT) group, intermediate dose fasudil treated(IDFT) group and Low dose fasudil treated (LDFT)group. 1h before surgery the rats received intraperitoneal injection normal saline 0.5ml ( sham group and AMI group) ,30mg/kg fasudil (HDFT group), 10mg/kg fasudil(IDFT group) and 1mg/kg fasudil(LDFT group). At 24 hours after coronary ligation,the rats were sacrificed.The myocardial infarction area and ischemia area were determined by evans-bule and TTC double staining.The cardiocyte apoptosis in the ischemia region was determined by TUNEL assay and the apoptotic index(AI) were calculated.The Bcl-2 and Bax protein expressions were measured by immunohistochemical staining.
Results: 1 Compared with the AMI group, the myocardial infarction area reduced obviously in HDF group and IDF group(P <0.01);There was not statistically significant between LDF group and AMI group(P >0.05);Compared with the LDF group, the myocardial infarction area reduced obviously in IDF group(P<0.01).
2 Compared with the Sham group, the expression of Bcl-2 reduced obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the expression of Bcl-2 increased obviously in HDF group and IDF group(P <0.01);There was not statistically significant between AMI group and LDF group(P >0.05);Compared with the IDF group, the expression of Bcl-2 increased obviously in HDF group(P<0.01). Compared with the LDF group, the expression of Bcl-2 increased obviously in LDF group(P<0.01).
3 Compared with the Sham group, the expression of Bax increased obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the expression of Bax reduced obviously in LDF group, IDF group and HDF group(P <0.01);Compared with the IDF group, the expression of Bax reduced obviously in HDF group(P<0.01). Compared with the LDF group, the expression of Bax reduced obviously in IDF group(P<0.01).
4 Compared with the Sham group, the cardiomyocyte apoptotic index increased obviously in AMI group, LDF group, IDF group and HDF group(P <0.01);Compared with the AMI group, the cardiomyocyte apoptotic index reduced obviously in LDF group, IDF group and HDF group(P <0.01);Compared with the IDF group, the cardiomyocyte apoptotic index reduced obviously in HDF group(P<0.01). Compared with the LDF group, the cardiomyocyte apoptotic index reduced obviously in IDF group(P<0.01).
Conclusion: Different Doses Fasudil intervention after AMI in rats can be illustnated as follows, (1) increase the expression of Bcl-2.(2) reduce the expression of Bax.(3) reduce the Cardiocyte apoptosis.(4) reduce the myocardial infarction area. These effects has dose-dependently, and the higer dose the better results.
引文
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22 Kanda T, Wakino S,Hayashi K, et al .Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kindey Int,2003,64:2009-2019
23 Mollnau H,Wendt M,Szocs K,et al.Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling.Circ Res,2002,90(4):E58-E65
24 Higashi M,Shimokawa H,Hattori T,et al.Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo:effect on endothelial NAD(P)H oxidase system.Circ Res,2003,93(8):767-775
25 Kandabashi T,Shimokawa H,Miyata K,et al.Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β.Circulation,2000,101:1319-1323
26 Kandabashi T,Shimokawa H,Miyata K,et al.Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol,2003,23:2209-2214
27 Mohri M,Shimokawa H,Hirakawa Y,et al.Rho-kinase inhbition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm.J Am Coll Cardiol,2003,41 (1):15-19
28 Otsuka T,Ibuki C,Suzuki T,et al.Vasodilatory effect of subsequent administration of fasudil,a Rho-kinase inhibitor,surpasses that ofnitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris.Circ J,2006,70 (4):402- 408
29 Shimokawa H,Hiramori K,Iinuma H,et al.Anti-anginal effect of fasudil,a Rho-kinase inhibitor,in patients with stable effort angina:a multicenter study.J Cardiovasc Pharmacol,2002,40 (5):751 - 761
30 Loch Macdonald R.Management of cerebral vasospasm.Neurosurg Rev,2006,29:179-193
31 Sasaki Y,Suzuki M,Hidaka H.The novel and specific Rho-kinase inhibitor(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopip-erazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol Ther,2002,93:225-232
32 Ecker A,Riemenschneider PA.Arteriographic demonstration of spasm of the intracranial arteries,with special reference to saccul ararterial aneurysms.J Neurosurg,1951,8:660-667
33 Watanabe Y,Faraci FM,Heistad DD,et al.Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol,2005,288 (6):2653-2658
34 Sato M,Tani E,Fujikawa H,et al.Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. Circ Res,2000,87:195-200
35 Wickman G,Lan C,Vollrath B.Functional roles of the rho/rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin:relevance to subarachnoid hemorrhage and vasospasm.Circ Res,2003,92:809-816
36 Lan C,Das D,Wloskowicz A,et al.Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C.Am J Physiol Heart Circ Physiol, 2004, 286: H165-H173
37 Feng J,Ito M,Kureishi Y,etal.Rho-associated kinase of chicken gizzard smooth muscle.J Biol Chem,1999,274:3744-3452
38 Bao W,Hu E,Tao L,etal.Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury.Cardiovasc Res,2004,61:548-558
39 Hashiba Y,Tosaka M,Saito N,etal.Vasorelaxing effect of the Rho-kinase inhibitor,Y-27632,in isolated canine basilar arteries. Neurol Res, 2007, 29: 485-489
40黄琳,李琴,王维亭,等.盐酸法舒地尔对血管舒缩功能的调节作用.中国药理学通报,2007,23(2):251-256
41 Tanaka K,Minami H,Kota M,etal.Treatment of cerebral vasospasm with intra-arterial fasudil hydrochloride.Neurosurgery,2005,56:214-223
42 Ishida T.Development of drug delivery system for intrathecal administration and its therapeutic effect on cerebral vasospasm and ischemia. Yakugaku Zasshi,2004,124:541-547
43 Zhao J,Zhou D,Guo J,et al.Effect of fasudil hydrochloride, a protein kinase inhibitor,on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage.Neurol Med Chir(Tokyo), 2006,46:421-428
44 Egge A,Waterloo K,Sjoholm H,et al.Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage.J Neurosurg, 2004,100(2):359-360
45 Budzyn K,Marley PD,Sobey CG.Opposing roles of endothelial and smooth muscle phosphatidy linositol 3-kinase in vasoconstriction:effects of rho-kinase and hypertension.J Pharmacol Exp Ther,2005, 313: 1248-1253
46 Faraci FM,Lamping KG,Modpickm L, et al.Cerebral vascular effects of angiotensin II:new insights from genetic models.J Cerebr Blood F Met, 2006,26 (4):449-455
47 Tolle M,Giebing G,Tietge UJ,etal.Diguanosine pentaphosphate:an endogenous activator of Rho-kinase possibly involved in blood pressure regulation. J Hypertens,2006,24:1991-2000
48 Ying Z,Jin L,Dorrance AM,etal.Increaseed expression of mRNA forregulator of G protein signaling domain-containing Rho guanine nucleotide exchange factors in aorta from stroke-prone spontaneously hypertensive rats.Am J Hypertens,2004,17:981-985
49 Chrissobolis S,Sobey CG.Evidence that Rho kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension Comparison with protein kinase C. Circ Res,2001,88:774-779
50 Uehata M,Ishizaki T,Satoh H,et el.Calcium sensitization of smooth muscle mediated by a Rho-associated protein-kinase in hypertension.Nature, 1997,389 (6654):990-994
51 Ito K, Hirooka Y, Kishi T,et al.Rho /Rho kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition.Hypertension,2004,43:156-162
52 Masumoto A,Hipooka Y,Shimokawa H,et el.Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension,2001,38 (6):1307-1310
53 Higashi M,Mukai Y,Matoba T,et al.Long-term inhibition of Rho-kinase suppresses angiotensin II -induced formation of coronary vascular lesions and cardiac hypertrophy in rats in vivo.Circulation, 2001,104 (suppl II) :II -325
54 Zhao ZQ,Budde JM,Morris C,et al.Adenosine attenuates reperfusion- induced apoptotic cell death by modulating expression of bcl-2 and Bax proteins.J Mol Cell Cardiol, 2001,33:57-68
55戴睿,曾秋棠,吴辉文.法舒地尔对急性心肌梗死大鼠心肌的保护作用.临床心血管病杂志,2008,24(7):537-539
56 Hattori T,Shimokawa H,Higashi M.Long-term inhibition of Rho kinase suppresses left ventricular remodeling after myocardial infarction in mice.Circulation,2004,109:2234-2239
57 Qvigstad E,Sjaastad I,Brattelid T,et al.Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart. Circ Res,2005,97:268-276
58 Hisaoka T,Yano M,Ohkusa T,et al.Enhancement of Rho/ Rho-kinase systerm in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure. Cardiovas Res,2001,49 (2):319-329
59 Wang YX,da Cunba V,Martin-McNulty B,et al.Inhibition of Rho-kinase by fasudil attenuated angiotensinⅡ-induced cardiac hypertrophy in apolipoprotein E deficient mice.Eur J Pharmacol,2005,512 (2-3):215-222
60张曼,曾定尹.法舒地尔对压力负荷心力衰竭大鼠的作用.中国医科大学学报,2004,33(6):484-486
61佟浩,张曼.不同剂量法舒地尔对压力负荷心力衰竭大鼠心肌细胞凋亡和凋亡相关基因表达的影响.中国实验动物学报,2007,15(5):376-379
62 Matsumoto Y,Uwatoku T,Oi K,etal.Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms.Arterioscler Thromb Vasc Biol,2004,24:181-186
63 Takeda K,Ichiki T,Tokunou T,et al.Critical role of rho-kinase and MEK/ERK pathways for angiotensinⅡ-induced plasminogen activator inhibitor type-1 gene expression.Arterioscler Thromb Vasc Biol,2001,21 (5):868-873
64 Worthylake RA,Lemoine S,Watson JM,et al.RhoA is required for monocyte tail retraction during transendothelial migration.J Cell Biol,2001,154 (1):147-160
65 Eto Y,Shimokawa H,Hiroki J,et al.Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs .Am J Physiol Heart Circ Physiol,2000,278 (6):H1744-H1750
66 Sawada N,Itoh H,Ueyama K,et al.Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries .Circulation,2000,101(17):2030-2033
67 Sauzeau V,Le Mellionnec E,Bertoglio J,et al.Human urotensinⅡ-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase.Circ Res,2001,88(11):1102-1104
68 Negoro N,Hoshiga M,Seto M,et al.The kinase inhibitor fasudil (HA-1077)reduces intimal hyperplasia through inhibiting migration and enhancing cell loss of vascular smooth muscle cells.Biochem Biophys Res Commun,1999,262(1):211-215
2 Leung T,Manser E,Tan L,et al .A novel serine/threonine kinase binding the Ras-related rhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem,1995,270 (49):29051-29054
3 Shiotani S,Shimada M,Suehiro T,et al.Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats. Transplantation,2004,78:375-382
4 Zhang YL,Zhou SX,Lei J,et al.Effects of perindopril on left ventricular remodeling and osteopontin expression in rats with myocardial infarction. South China journal of Cardiovascular Disease,2007,8(3):159-165
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8张春蕾,王跃民,李源等.大鼠慢性心肌梗死模型的制作.心脏杂志,2005,17(6):539-541
9刘宏宇,王祥贵,李长运,等.针刺心肌打孔与激光心肌血运重建术对急性心肌缺血的影响.临床心血管病杂志,2004,20 (1) :36-38
10 Budzyn K, Marley PD, Sobey CG.Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol Sci. 2006,27(2): 97-104
11 Masumoto A,Mohri M,Shimokawa H,et al.Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation, 2002,105:1545-1547
12 Nakamura K,Nishimura J,Hirano K,et al.Hydroxyfasudil,an active metabolite of fasudil hydrochloride,relaxes the rabbit basilar artery by disinhibition of myosin light chain phosphatase.J Cereb Blood Flow Metab,2001,21:876-885
13戴睿,曾秋棠,吴辉文.法舒地尔对急性心肌梗死大鼠心肌的保护作用.临床心血管病杂志,2008,24(7):537-539
14 Misao J,Hayakawa Y,Ohno M,et al.Expression of Bcl-2 protein,an inhibitor of apoptosis,and Bax,an accelerator of apoptosis,in ventricular myocytes of human hearts with myocardial infarction. Circulation, 1996, 94(7):1506-1512
15 Olivetti G,Abbi R,Quaini F,et al.Apoptosis in the failing human heart[J].N Eng J Med,1997, 336(16):1131-1141
16 Cheng W,Kajstura J,Nitahara JA,et al.Programmed myocyte cell death affects the viable myocardium after in farction in rats[J]. Exp Cell Res,1996, 226(2):316-327
17佟浩,张曼.不同剂量法舒地尔对压力负荷心力衰竭大鼠心肌细胞凋亡和凋亡相关基因表达的影响.中国实验动物学,2007,15(5):376-379
18吴强,李隆贵,耿召华.心肌梗死后心衰大鼠心肌细胞凋亡和凋亡相关基因表达的变化.第三军医大学学报,2002,24(4):434-436
19 Wenker D,Nguyen KT,Khine CC,et al.Myocyte apoptosis is sufficient to cause dilated cardiomyopathy J.ciurculation,1999,100:11
20 Li Z,Bing OH L,Long X,et al.Increased cardiomyocyte apoptosis during the transition of heart failure in the spontaneously hypertensiverat J.Am J Physiol,1997,272:H 2313-2319
21陈跃峰,杨跃进,阮英茆,等.大鼠急性心肌梗死后的心肌细胞凋亡和凋亡相关基因表达的变化.Chinese Journal of Pathophysiology,2006,22(10): 1943-1948
1 Leung T,Manser E,Tan L,et al .A novel serine/threonine kinase binding the Ras-related rhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem,1995,270(49):29051-29054
2 Shimokawa H,Takeshita A.Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol,2005,25(9):1767 -1775
3 Matsui T, Amano M,Yamamoto T,et al.Rho-associated kinase,a novel serine/ threonine kinase,as a putative target for small GTP binding protein Rho. EMBO J,1996,15 (9):2208 -2216
4 Doran JD,Liu X,Taslimi P,et al.New insights into the structure-function relationships of Rho-associated kinase:a thermodynamic and hydrodynamic study of the dimer-to-monomer transition and its kinetic implications. Biochem J,2004,384:255-262
5 Riento K,Ridley AJ.Rocks:Multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol,2003,4(6):446-456
6 Amano M,Chihara K,Nakamura N,et al.The COOH terminus of Rho- kinase negatively regulates Rho-kinase activity. J Biol Chem,1999, 274 (45) :32418-32424
7 Solaro RJ. Myosin light chain phosphatase:a Cinderella of cellular signaling. Circ Res, 2000, 87(3): 173-175
8 Fukata Y,Oshiro N,Kinoshita N,et al.Phosphorylation of adducin by Rho-kinase plays a crucial role in cell motility. J Cell Biol,1999,145(2):347-361
9 Amano M,Fukata Y,Kaibuchi K,et al.Regulation and functions of Rho-associated kinase.Exp Cell Res,2000,261(1):44-51
10 Amano M,Ito M,Kimura K,et al.Phosphorylation and activation of myosin by rho-associated kinase (Rho-kinase). J Biol Chem,1996,271 (34):20246-20249
11 Bhadriraju K,Elliott JT, Nguyen M,et al.Quantifying myosin light chain phosphorylation in single adherent cells with automated fluorescence microscopy. BMC Cell Biol.2007,8: 43
12 Masumoto A,Mohri M,Shimokawa H,et al.Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation, 2002,105:1545-1547
13 Nakamura K,Nishimura J,Hirano K,et al.Hydroxyfasudil,an active metabolite of fasudil hydrochloride,relaxes the rabbit basilar artery by disinhibition of myosin light chain phosphatase.J Cereb Blood Flow Metab,2001,21:876-885
14 Shimokawa H,Morishige K,Miyata K,et al.Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo.Cardiovas Res,2001,51 (1) 169-177
15 Morishige K,Shimokawa H,Eto Y,et al.Adenovirus-mediated transfer of dominant-negative Rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo.Arteroscler Thromb Vasc Biol,2001,21(4):548-554
16 Wolfrum S,Dendorfer A,Rikitake Y,et al .Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection.Arterioscler Thromb Vasc Biol,2004,24 (10):1842-1847
17 Shah DI,Singh M.Effect of fasudil on macrovascular disorder-induced endothelial dysfunction.Can J Physiol Pharmacol,2006,84(8-9):835-845
18 Mallat Z,Gojova A,Sauzeau V,et al.Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice.CircRes,2003,93:884-888
19 Seasholtz TM,Majumdar M,Kaplan DD,et al.Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and miration.Circ Res,1999,84(10):1186-1193
20 Nakayama M,Amano M,Katsumi A,et al.Rho-kinase and myosinⅡactivities are required for cell type and environment specific migration.Genes Cells,2005,10:107-117
21 Kanda T,Hayashi K,Wakino S,et al.Role of Rho-kinase and p27 in angiotensinⅡ-induced vascular injury. Hypertension, 2005,45:724-729
22 Kanda T, Wakino S,Hayashi K, et al .Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kindey Int,2003,64:2009-2019
23 Mollnau H,Wendt M,Szocs K,et al.Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling.Circ Res,2002,90(4):E58-E65
24 Higashi M,Shimokawa H,Hattori T,et al.Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo:effect on endothelial NAD(P)H oxidase system.Circ Res,2003,93(8):767-775
25 Kandabashi T,Shimokawa H,Miyata K,et al.Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β.Circulation,2000,101:1319-1323
26 Kandabashi T,Shimokawa H,Miyata K,et al.Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol,2003,23:2209-2214
27 Mohri M,Shimokawa H,Hirakawa Y,et al.Rho-kinase inhbition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm.J Am Coll Cardiol,2003,41 (1):15-19
28 Otsuka T,Ibuki C,Suzuki T,et al.Vasodilatory effect of subsequent administration of fasudil,a Rho-kinase inhibitor,surpasses that ofnitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris.Circ J,2006,70 (4):402- 408
29 Shimokawa H,Hiramori K,Iinuma H,et al.Anti-anginal effect of fasudil,a Rho-kinase inhibitor,in patients with stable effort angina:a multicenter study.J Cardiovasc Pharmacol,2002,40 (5):751 - 761
30 Loch Macdonald R.Management of cerebral vasospasm.Neurosurg Rev,2006,29:179-193
31 Sasaki Y,Suzuki M,Hidaka H.The novel and specific Rho-kinase inhibitor(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopip-erazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol Ther,2002,93:225-232
32 Ecker A,Riemenschneider PA.Arteriographic demonstration of spasm of the intracranial arteries,with special reference to saccul ararterial aneurysms.J Neurosurg,1951,8:660-667
33 Watanabe Y,Faraci FM,Heistad DD,et al.Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol,2005,288 (6):2653-2658
34 Sato M,Tani E,Fujikawa H,et al.Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. Circ Res,2000,87:195-200
35 Wickman G,Lan C,Vollrath B.Functional roles of the rho/rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin:relevance to subarachnoid hemorrhage and vasospasm.Circ Res,2003,92:809-816
36 Lan C,Das D,Wloskowicz A,et al.Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C.Am J Physiol Heart Circ Physiol, 2004, 286: H165-H173
37 Feng J,Ito M,Kureishi Y,etal.Rho-associated kinase of chicken gizzard smooth muscle.J Biol Chem,1999,274:3744-3452
38 Bao W,Hu E,Tao L,etal.Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury.Cardiovasc Res,2004,61:548-558
39 Hashiba Y,Tosaka M,Saito N,etal.Vasorelaxing effect of the Rho-kinase inhibitor,Y-27632,in isolated canine basilar arteries. Neurol Res, 2007, 29: 485-489
40黄琳,李琴,王维亭,等.盐酸法舒地尔对血管舒缩功能的调节作用.中国药理学通报,2007,23(2):251-256
41 Tanaka K,Minami H,Kota M,etal.Treatment of cerebral vasospasm with intra-arterial fasudil hydrochloride.Neurosurgery,2005,56:214-223
42 Ishida T.Development of drug delivery system for intrathecal administration and its therapeutic effect on cerebral vasospasm and ischemia. Yakugaku Zasshi,2004,124:541-547
43 Zhao J,Zhou D,Guo J,et al.Effect of fasudil hydrochloride, a protein kinase inhibitor,on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage.Neurol Med Chir(Tokyo), 2006,46:421-428
44 Egge A,Waterloo K,Sjoholm H,et al.Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage.J Neurosurg, 2004,100(2):359-360
45 Budzyn K,Marley PD,Sobey CG.Opposing roles of endothelial and smooth muscle phosphatidy linositol 3-kinase in vasoconstriction:effects of rho-kinase and hypertension.J Pharmacol Exp Ther,2005, 313: 1248-1253
46 Faraci FM,Lamping KG,Modpickm L, et al.Cerebral vascular effects of angiotensin II:new insights from genetic models.J Cerebr Blood F Met, 2006,26 (4):449-455
47 Tolle M,Giebing G,Tietge UJ,etal.Diguanosine pentaphosphate:an endogenous activator of Rho-kinase possibly involved in blood pressure regulation. J Hypertens,2006,24:1991-2000
48 Ying Z,Jin L,Dorrance AM,etal.Increaseed expression of mRNA forregulator of G protein signaling domain-containing Rho guanine nucleotide exchange factors in aorta from stroke-prone spontaneously hypertensive rats.Am J Hypertens,2004,17:981-985
49 Chrissobolis S,Sobey CG.Evidence that Rho kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension Comparison with protein kinase C. Circ Res,2001,88:774-779
50 Uehata M,Ishizaki T,Satoh H,et el.Calcium sensitization of smooth muscle mediated by a Rho-associated protein-kinase in hypertension.Nature, 1997,389 (6654):990-994
51 Ito K, Hirooka Y, Kishi T,et al.Rho /Rho kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition.Hypertension,2004,43:156-162
52 Masumoto A,Hipooka Y,Shimokawa H,et el.Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension,2001,38 (6):1307-1310
53 Higashi M,Mukai Y,Matoba T,et al.Long-term inhibition of Rho-kinase suppresses angiotensin II -induced formation of coronary vascular lesions and cardiac hypertrophy in rats in vivo.Circulation, 2001,104 (suppl II) :II -325
54 Zhao ZQ,Budde JM,Morris C,et al.Adenosine attenuates reperfusion- induced apoptotic cell death by modulating expression of bcl-2 and Bax proteins.J Mol Cell Cardiol, 2001,33:57-68
55戴睿,曾秋棠,吴辉文.法舒地尔对急性心肌梗死大鼠心肌的保护作用.临床心血管病杂志,2008,24(7):537-539
56 Hattori T,Shimokawa H,Higashi M.Long-term inhibition of Rho kinase suppresses left ventricular remodeling after myocardial infarction in mice.Circulation,2004,109:2234-2239
57 Qvigstad E,Sjaastad I,Brattelid T,et al.Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart. Circ Res,2005,97:268-276
58 Hisaoka T,Yano M,Ohkusa T,et al.Enhancement of Rho/ Rho-kinase systerm in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure. Cardiovas Res,2001,49 (2):319-329
59 Wang YX,da Cunba V,Martin-McNulty B,et al.Inhibition of Rho-kinase by fasudil attenuated angiotensinⅡ-induced cardiac hypertrophy in apolipoprotein E deficient mice.Eur J Pharmacol,2005,512 (2-3):215-222
60张曼,曾定尹.法舒地尔对压力负荷心力衰竭大鼠的作用.中国医科大学学报,2004,33(6):484-486
61佟浩,张曼.不同剂量法舒地尔对压力负荷心力衰竭大鼠心肌细胞凋亡和凋亡相关基因表达的影响.中国实验动物学报,2007,15(5):376-379
62 Matsumoto Y,Uwatoku T,Oi K,etal.Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms.Arterioscler Thromb Vasc Biol,2004,24:181-186
63 Takeda K,Ichiki T,Tokunou T,et al.Critical role of rho-kinase and MEK/ERK pathways for angiotensinⅡ-induced plasminogen activator inhibitor type-1 gene expression.Arterioscler Thromb Vasc Biol,2001,21 (5):868-873
64 Worthylake RA,Lemoine S,Watson JM,et al.RhoA is required for monocyte tail retraction during transendothelial migration.J Cell Biol,2001,154 (1):147-160
65 Eto Y,Shimokawa H,Hiroki J,et al.Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs .Am J Physiol Heart Circ Physiol,2000,278 (6):H1744-H1750
66 Sawada N,Itoh H,Ueyama K,et al.Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries .Circulation,2000,101(17):2030-2033
67 Sauzeau V,Le Mellionnec E,Bertoglio J,et al.Human urotensinⅡ-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase.Circ Res,2001,88(11):1102-1104
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