Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy
Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy
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DOI：
10.1073/pnas.0905485106
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发表时间：
2009-07-07
影响因子：
11.1
通讯作者：
Roderick, H. Llewelyn
中科院分区：
文献类型：
--
作者：
Harzheim, Dagmar;Movassagh, Mehregan;Roderick, H. Llewelyn
心脏肥厚是心脏对血流动力学需求增加或损伤的生长反应。伴随心脏增大的是Ca2+信号的重塑。由于其在每次心跳期间控制心肌细胞收缩的基本作用，Ca2+通量的改变显着影响心输出量并促进心律失常的发展。使用自发性高血压大鼠（SHRs）的心肌细胞，我们证明通过肌醇1,4,5-三磷酸受体（InsP(3)Rs）增加Ca2+释放有助于肥厚肌细胞更大的兴奋收缩偶联（ECC）介导的Ca2+瞬态特征，并且是由InsP(3)或内皮素-1 （ET-1）引起的ECC介导的Ca2+瞬态和收缩更有效增强的基础。这与连接肌浆网中InsP(3)R表达的增加有关。由于它们与该区域的ryanodine受体（RyRs）非常接近，通过InsP(3)Rs增强Ca2+释放有助于使RyRs敏感，从而增加舒张期Ca2+水平，收缩外Ca2+瞬态的发生率，并诱导ec介导的Ca2+升高。与细胞质中InsP(3)R表达和Ca2+瞬态振幅的增加不同，细胞核中InsP(3)R表达和ecc介导的Ca2+瞬态在肥大期间没有改变。在缺血性扩张型心肌病心力衰竭患者的心脏以及主动脉带状肥厚小鼠的心脏中也检测到InsP(3)R2表达升高。我们的数据表明，InsP(3)R表达的增加是心脏病期间Ca2+信号重塑的一般机制，特别是在肥厚期间引发室性心律失常。
Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca2+ signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca2+ fluxes significantly impact on cardiac output and facilitate the development of arrhythmias. Using cardiomyocytes from spontaneously hypertensive rats (SHRs), we demonstrate that an increase in Ca2+ release through inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) contributes to the larger excitation contraction coupling (ECC)- mediated Ca2+ transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECC-mediated Ca2+ transients and contraction elicited by InsP(3) or endothelin-1 (ET-1). Responsible for this is an increase in InsP(3)R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca2+ release through InsP(3)Rs served to sensitize RyRs, thereby increasing diastolic Ca2+ levels, the incidence of extra-systolic Ca2+ transients, and the induction of ECC-mediated Ca2+ elevations. Unlike the increase in InsP(3)R expression and Ca2+ transient amplitude in the cytosol, InsP(3)R expression and ECC-mediated Ca2+ transients in the nucleus were not altered during hypertrophy. Elevated InsP(3)R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. Our data establish that increased InsP(3)R expression is a general mechanism that underlies remodeling of Ca2+ signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.