Department of Epidemiology and Preventive Medicine, National Health Medical Research Council Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia.
Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H608-13. doi: 10.1152/ajpheart.00942.2009. Epub 2009 Dec 11.
The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.
尿鸟素 II（U-II）是一种血管活性肽，很可能在导致心力衰竭的心脏重构中发挥关键的因果作用。然而，其具体对舒张功能障碍和下游细胞内信号转导的贡献仍未得到解决。本研究探讨了慢性 U-II 输注对正常大鼠心脏结构和功能的影响。在细胞培养研究中评估了 Rho 激酶（ROCK）信号对这些病理生理变化的贡献。在超声心动图衍生的多普勒指数上，慢性高剂量 U-II 输注 4 周显著损害了大鼠的舒张功能，包括 E 波减速时间（载体 56.7 +/- 3.3 ms，U-II 118.0 +/- 21.5 ms；P < 0.01）和二尖瓣瓣环峰值早期/晚期舒张组织速度（载体 2.01 +/- 0.19 ms，U-II 1.04 +/- 0.25 ms；P < 0.01）。输注较低剂量的 U-II（1 nmol.kg(-1).h(-1)）也产生了类似的变化。舒张功能障碍伴随着分子[实时 PCR 显示原胶原-α(1)(I)基因表达显著增加]和形态学（总胶原增加，P < 0.05，以及 I 型胶原蛋白沉积增加，P < 0.001）证据表明，高剂量 U-II 输注后左心室（LV）纤维化。ROCK 抑制剂 GSK-576371（10(-7) 至 10(-5) M）对 U-II（10(-7) M）刺激的心肌成纤维细胞胶原合成和心肌细胞蛋白合成表现出浓度依赖性抑制。慢性 U-II 输注导致 LV 纤维化引起舒张功能障碍。体外数据表明，这可能部分是通过 ROCK 依赖途径发生的。
