Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction
Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction
复制标题
DOI：
10.1152/ajpheart.01078.2007
复制
发表时间：
2008-04-01
影响因子：
4.8
通讯作者：
Krum, Henry
中科院分区：
文献类型：
--
作者：
Phrommintikul, Arintaya;Tran, Lavinia;Krum, Henry
RhoA-Rho激酶（ROCK）信号通路在心血管疾病中具有重要作用。然而，Rho激酶抑制对压力过载引起的心脏肥厚（POH）和相关舒张功能障碍的影响尚未得到评估。本研究检测了一种选择性ROCK抑制剂（GSK-576371）在肾上腹主动脉收缩诱导的POH模型中的作用。将POH大鼠分为4组：1 （GSK 1, n = 9）或3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg.kg（-1）。第1天（1天）雷米普利（n = 10）或载体（n = 11）治疗4周。假动物（n = 11）接受无绑带手术。术前和治疗后进行超声心动图检查，并在研究结束时获得血流动力学数据。超声心动图显示，与假动物相比，POH +载体治疗后左心室（LV）相对壁厚增加。GSK-576371和雷米普利两剂均可减毒。用GSK-576371治疗后，患者的舒张参数出现异常，包括二尖瓣流入E波减速时间、等容松弛时间和二尖瓣环速度，这些参数与假手术值呈剂量依赖性恢复。与假手术相比，POH +载药组左室舒张压升高（6.9 +/- 0.7 vs. 3.2 +/- 0.7 mmHg, P = 0.008）， GSK 3和雷米普利组左室舒张压降低（分别为1.7 +/- 0.7,P < 0.01和2.9 +/- 0.6 mmHg, P < 0.01）。与假动物相比，POH +载药组左室I型胶原沉积增加（32.2%,P < 0.01）， GSK 1 （21.7%, P < 0.05）、GSK 3 （23.8%, P < 0.01）、雷米普利（35.5%,P < 0.01）组左室I型胶原沉积明显减少。这些结果表明，ROCK抑制改善了POH的左室几何形状，减少了胶原沉积，同时改善了舒张功能。
The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK-576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg.kg(-1).day(-1) ramipril (n = 10) or vehicle (n = 11) treatment for 4 wk. Sham animals (n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 +/- 0.7 vs. 3.2 +/- 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 +/- 0.7, P < 0.01 and 2.9 +/- 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.