Gregory Kimberly N, Ginsburg Kenneth S, Bodi Ilona, Hahn Harvey, Marreez Yehia M A, Song Qiujing, Padmanabhan Prabhu A, Mitton Bryan A, Waggoner Jason R, Del Monte Federica, Park Woo Jin, Dorn Gerald W, Bers Donald M, Kranias Evangelia G
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575, USA.
J Mol Cell Cardiol. 2006 May;40(5):653-65. doi: 10.1016/j.yjmcc.2006.02.003.
Defects in the pathways that regulate cardiac sarcoplasmic reticulum (SR) calcium (Ca) cycling represent prime targets for driving the deterioration of function and progression to heart failure. We hypothesized that the histidine-rich Ca binding protein (HRC) in the SR may be involved in SR Ca cycling and that alterations in HRC levels would result in abnormal cardiac Ca homeostasis. In order to test this hypothesis, we generated transgenic mice with cardiac overexpression (3-fold) of HRC. Increased cardiac HRC levels were associated with impaired SR Ca uptake rates (35%) and attenuated cardiomyocyte Ca transient decay (38%), without alterations in peak Ca transients or SR Ca load. The depressed SR Ca sequestration was associated with attenuated rate of Ca extrusion via Na-Ca exchange. Triadin protein expression levels and L-type Ca channel current density were increased, while the channel inactivation kinetics were not altered. Impaired SR Ca uptake and delayed Ca decline rates triggered hypertrophy and compromised the heart's responses to increased stress by either hemodynamic overload or the aging process. By 18 months of age, cardiac remodeling deteriorated to congestive heart failure in transgenic mice. Collectively, these data suggest that HRC may be an integral regulatory protein involved in cardiac muscle SR Ca uptake and Ca homeostasis.
调节心肌肌浆网（SR）钙（Ca）循环的信号通路缺陷是导致心脏功能恶化和心力衰竭进展的主要靶点。我们推测，肌浆网中富含组氨酸的钙结合蛋白（HRC）可能参与肌浆网钙循环，HRC水平的改变会导致心脏钙稳态异常。为了验证这一假设，我们构建了心脏过表达（3倍）HRC的转基因小鼠。心脏HRC水平升高与肌浆网钙摄取率受损（35%）和心肌细胞钙瞬变衰减减弱（38%）相关，而钙瞬变峰值或肌浆网钙负荷无变化。肌浆网钙螯合能力降低与通过钠钙交换的钙外排速率减弱有关。三联蛋白表达水平和L型钙通道电流密度增加，而通道失活动力学未改变。肌浆网钙摄取受损和钙下降速率延迟引发心肌肥大，并损害心脏对血流动力学过载或衰老过程引起的应激增加的反应。到18月龄时，转基因小鼠的心脏重塑恶化为充血性心力衰竭。总体而言，这些数据表明HRC可能是参与心肌肌浆网钙摄取和钙稳态的一种重要调节蛋白。
