Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway
Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway
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DOI：
10.1152/ajpheart.00654.2010
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发表时间：
2011-06-01
影响因子：
4.8
通讯作者：
Kukreja, Rakesh C.
中科院分区：
文献类型：
--
作者：
Chau, Vinh Q.;Salloum, Fadi N.;Kukreja, Rakesh C.
Chu VQ，Salloum FN，Hoke NN，Abbate A，Kukreja RC。西地那非缓解心力衰竭的进展包括抑制RhoA/Rho-Kinase通路。Am J Physiol心圈Physiol 300：H2 272-H2 279,2011。2011年3月11日首次出版；DOI：10.1152/ajpheart.00654.2010。-在永久性阻断左前降支冠状动脉后立即用西地那非长期抑制磷酸二酯酶-5被证明可以限制小鼠的缺血性心力衰竭(HF)。为了模拟更临床的情况，我们假设在心肌梗死(MI)后3天开始使用西地那非治疗也可以通过抑制RhoA/Rho-Kinase途径来减少心力衰竭的进展。成年雄性ICR小鼠在永久性冠状动脉左前降支结扎后第3天缩短率>25%，连续给予生理盐水(容量匹配，ip，2次/d)或西地那非(21 mg/kg，ip，2次/d)25d。超声心动图显示，在心肌梗死后7天和28天，西地那非治疗组与生理盐水治疗组相比，左心室短轴缩短率、左室舒张末期扩张明显减少(P<；0.05)。分别用Masson‘s三染色法和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法(TUNEL)检测的肝纤维化和细胞凋亡在西地那非治疗的小鼠中均有减轻(P<；0.05与生理盐水相比)。Western印迹分析显示，西地那非治疗后Bcl2/Bax比值增加(P<；0.05与生理盐水相比)。活性检测显示西地那非介导的PKG在治疗后1天被激活(P<；0.05与假手术组和生理盐水组比较)。与生理盐水处理相比，PKG激活与西地那非对Rho激酶的抑制有关(P<；0.05)，而KT-5823对PKG的抑制可阻断西地那非的这种抑制作用。总而言之，我们的研究结果首次表明，在心肌梗死后3天开始的慢性西地那非治疗可以减轻左心功能障碍，而不是独立于其心肌梗死保护作用，并且这种心脏保护涉及到抑制RhoA/Rho-Kinase途径。西地那非可能是治疗晚期心力衰竭的一种有前景的治疗工具。
Chau VQ, Salloum FN, Hoke NN, Abbate A, Kukreja RC. Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway. Am J Physiol Heart Circ Physiol 300: H2272-H2279, 2011. First published March 11, 2011; doi: 10.1152/ajpheart.00654.2010.-Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI (P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice (P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment (P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment (P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase (P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.