In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure
In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure
复制标题
DOI：
10.1016/j.yjmcc.2012.11.013
复制
发表时间：
2013-04-01
影响因子：
5
通讯作者：
Lucchesi, Pamela A.
中科院分区：
文献类型：
--
作者：
Guggilam, Anuradha;Hutchinson, Kirk R.;Lucchesi, Pamela A.
容量过载（VO）的心脏经历进行性心室肥厚导致慢性心力衰竭，对β -肾上腺素能激动剂无反应。本研究比较了终末期VO心力衰竭（HF）大鼠左心室（LV）和离体心肌细胞的收缩力和β -肾上腺素能反应性。成年雄性Sprague-Dawley大鼠在主动脉腔瘘（ACF）或假手术后21周进行研究。超声心动图显示，与假手术相比，终末期ACF的分数缩短减少，左室直径增加，偏心扩张指数降低。血流动力学测量显示收缩期末期压力-容积关系斜率减小，提示收缩功能不全。ACF分离的左室肌细胞表现出肌节缩短峰和动力学降低。在ACF肌细胞中，Ca2 +瞬态振幅和动力学均增加，而在与收缩和松弛期相关的Ca2 +综合曲线下没有变化。在ACF中观察到ryanodine受体和磷蛋白磷酸化的增加，以及SERCA2水平的降低。这些变化与β -肌凝蛋白重链、心肌肌钙蛋白I和心肌肌凝蛋白结合蛋白c的表达降低有关。体内对-肾上腺素能刺激的肌力反应在ACF中减弱。有趣的是，在β -肾上腺素能激动剂的作用下，ACF肌细胞表现出与sham相似的峰值缩短。间隙连接蛋白connexin-43的表达减少，但Ser-368位点的磷酸化增加。这些变化与Src和ZO-1的改变有关。总之，这些数据表明体内和体外条件下β -肾上腺素能反应性的脱节可能与肌丝Ca2 +敏感性和连接蛋白43降解的改变有关。(C) 2012 Elsevier Ltd.版权所有。
Hearts in volume overload (VO) undergo progressive ventricular hypertrophy resulting in chronic heart failure that is unresponsive to beta-adrenergic agonists. This study compared left ventricular (LV) and isolated cardiomyocyte contractility and beta-adrenergic responsiveness in rats with end-stage VO heart failure (HF). Adult male Sprague-Dawley rats were studied 21 weeks after aortocaval fistula (ACF) or sham surgery. Echocardiography revealed decreased fractional shortening accompanied by increased LV chamber diameter and decreased eccentric dilatation index at end-stage ACF compared to sham. Hemodynamic measurements showed a decrease in the slope of end-systolic pressure-volume relationship, indicating systolic dysfunction. Isolated LV myocytes from ACF exhibited decreased peak sarcomere shortening and kinetics. Both Ca2 + transient amplitude and kinetics were increased in ACF myocytes, with no change under the integrated Ca2 + curves relating to contraction and relaxation phases. Increases in ryanodine receptor and phospholamban phosphorylation, along with a decrease in SERCA2 levels, were observed in ACF. These changes were associated with decreased expression of beta-myosin heavy chain, cardiac troponin I and cardiac myosin binding protein-C. In vivo inotropic responses to beta-adrenergic stimulation were attenuated in ACF. Interestingly, ACF myocytes exhibited a similar peak shortening to those of sham in response to a beta-adrenergic agonist. The protein expression of the gap junction protein connexin-43 was decreased, although its phosphorylation at Ser-368 increased. These changes were associated with alterations in Src and ZO-1. In summary, these data suggest that the disconnect in beta-adrenergic responsiveness between in vivo and in vitro conditions may be associated with altered myofilament Ca2 + sensitivity and connexin-43 degradation. (C) 2012 Elsevier Ltd. All rights reserved.