Hypertension 2011 Dec;58 (6): 1099-110. [IF:6.908]
Ryanodine receptor type 2 is required for the development of pressure overload-induced cardiac hypertrophy.
Zou Y , Liang Y , Gong H , Zhou N , Ma H , Guan A , Sun A , Wang P , Niu Y , Jiang H , Takano H , Toko H , Yao A , Takeshima H , Akazawa H , Shiojima I , Wang Y , Komuro I , Ge J .
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Rd, Shanghai 200032, China.
上海市心血管病研究所，复旦大学附属中山医院
Abstract
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.
摘要：
兰尼碱2型受体(RyR-2)介导Ca(2+)从肌浆网释放并促进心肌收缩功能。然而，RyR-2在心肌肥厚的发展中所起的作用尚不完全清楚。研究中分别分析了RyR-2(+/-)和野生型小鼠RyR-2基因是否有减少。基线时，RyR-2(+/-)和野生型小鼠心脏和心肌细胞心态以及心肌收缩没有差别，但是，肌浆网释放Ca(2+)损伤RyR-2(+/-)心肌细胞。经历3周的压力负荷，该压力是由主动脉横纹肌收缩产生的，RyR-2(+/-)小鼠心肌细胞Ca(2+)的瞬间浓度减少更多，心脏收缩时细胞内Ca(2+)浓度增加、？百分率缩短，RyR-2(+/-)小鼠心脏显示更少的适应性心肌肥大，纤维化和收缩能力减少较少，更多的细胞凋亡，更少的心肌细胞自我吞噬。与野生型相比，血管生成减少相似。而且主动脉介导的横纹肌收缩导致磷酸酶，胞外信号调节蛋白激酶、蛋白激酶B/ Akt活化增强，而不是钙调蛋白依赖蛋白激酶，野生型小鼠心脏下调的指标，在RyR-2(+/-)是没有的，这暗示在压力负荷下RyR-2是钙磷酶、胞外信号调节蛋白激酶、蛋白激酶B/ Akt的调控子，而不是钙调蛋白依赖蛋白激酶。总之，数据显示压力负荷下通过肌浆网Ca(2+)释放，RyR-2有助于心肌肥大的发展，心脏功能的自我适应，钙激酶活化，胞外信号调节蛋白激酶，Akt和心肌细胞生存。
