Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Rd, Shanghai 200032, China.
Hypertension. 2011 Dec;58(6):1099-110. doi: 10.1161/HYPERTENSIONAHA.111.173500. Epub 2011 Oct 10.
Ryanodine receptor type 2 (RyR-2) mediates Ca(2+) release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2(+/-) and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2(+/-) and wild-type mice, although Ca(2+) release from sarcoplasmic reticulum was impaired in isolated RyR-2(+/-) cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2(+/-) cardiomyocytes displayed more reduction of Ca(2+) transient amplitude, rate of an increase in intracellular Ca(2+) concentration during systole, and percentile of fractional shortening, and hearts of RyR-2(+/-) mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca(2+)/calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2(+/-) one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca(2+) release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival.
肌质网钙释放通道蛋白 2 型（RyR-2）介导肌质网内钙离子释放，对心肌收缩功能有重要作用。然而，RyR-2 在心肌肥厚发展中的作用尚不完全清楚。本研究构建 RyR-2 基因敲除（RyR-2(+/-)和野生型）小鼠，观察 RyR-2 在心脏结构和功能中的作用。在基础状态下，RyR-2(+/-)和野生型小鼠的心肌细胞和心脏形态以及心脏收缩功能没有差异，尽管 RyR-2(+/-)心肌细胞肌质网钙离子释放减少。在主动脉缩窄诱导的 3 周压力超负荷期间，RyR-2(+/-)心肌细胞的钙离子瞬变幅度、收缩期细胞内钙离子浓度增加率和缩短分数的百分比较野生型降低，RyR-2(+/-)小鼠的心脏表现出代偿性肥厚、纤维化和收缩功能减少，心肌细胞凋亡增加，自噬减少，血管生成减少。此外，主动脉缩窄诱导的野生型小鼠心脏中钙调神经磷酸酶、细胞外信号调节激酶和蛋白激酶 B/蛋白激酶 Akt 的激活增加，但钙调蛋白依赖性蛋白激酶 II 及其下游靶点的激活没有增加，而 RyR-2(+/-)小鼠的这些改变被消除，表明 RyR-2 是钙调神经磷酸酶、细胞外信号调节激酶和 Akt 激活的调节因子，但不是钙调蛋白依赖性蛋白激酶 II 激活的调节因子。综上所述，我们的数据表明，RyR-2 通过调节肌质网钙离子释放、钙调神经磷酸酶、细胞外信号调节激酶和蛋白激酶 Akt 的激活以及心肌细胞存活，促进压力超负荷时心脏肥厚的发展和心脏功能的适应。
