Angiotensin receptor blockade improves the net balance of cardiac Ca2+ handling-related proteins in sympathetic hyperactivity-induced heart failure
Angiotensin receptor blockade improves the net balance of cardiac Ca2+ handling-related proteins in sympathetic hyperactivity-induced heart failure
复制标题
DOI：
10.1016/j.lfs.2011.01.009
复制
发表时间：
2011-03-28
期刊：
影响因子：
6.1
通讯作者：
Brum, Patricia C.
中科院分区：
文献类型：
--
作者：
Ferreira, Julio C. B.;Moreira, Jose B. N.;Brum, Patricia C.
目的：血管紧张素II 1型（AT 1）受体阻滞剂（ARB）治疗心力衰竭（HF）的临床获益包括心脏抗重塑和改善心室功能。然而，ARB对心室功能益处的细胞机制需要更好地阐明。在本论文中，我们评估了AT 1受体阻断对缺乏α（2A）和α（2C）肾上腺素受体的小鼠心脏中Ca 2+处理蛋白的净平衡的影响（alpha（2A）/alpha（2C）ARKO），其发展交感神经过度活跃（SH）诱导的HF。C57 BL 6/J遗传背景中的雄性野生型（WT）和同源α（2A）/α（2C）ARKO小鼠队列（5-7月龄）随机分配接受安慰剂或ARB（氯沙坦，10 mg/kg，持续8周）。通过超声心动图评估心室功能（VF），通过计算机辅助形态测量系统评估心肌细胞宽度和心室纤维化。通过蛋白质印迹分析肌浆网Ca 2 + ATP酶（SERCA 2）、受磷蛋白（PLN）、磷酸-Ser（16）-PLN、磷酸-Thr（17）-PLN、磷酸酶1（PP 1）、Na+-Ca 2+交换器（NCX）、Ca 2 +/钙调蛋白依赖性蛋白激酶11（CaMKII）和磷酸-Thr（286）-CaMKII。α（2A）/α（2C）ARKO小鼠表现出心室功能障碍、心肌细胞肥大和心脏纤维化，这是由于SERCA 2降低和磷酸化-Thr（17）-PLN、CaMKII、磷酸化-Thr（286）-CaMKII和NCX水平升高所致。ARB诱导了抗心脏重塑作用，并改善了α（2A）/α（2C）ARKO中的VF，与SERCA 2和磷酸化Ser（16）-PLN水平以及SERCA 2：NCX比值增加相关。此外，ARB降低磷酸化Thr（17）-PLN水平，并重新建立NCX，CaMKII和磷酸化Thr（286）-CaMKII向WT水平。(c)2011 Elsevier Inc. All rights reserved.
Aims: The clinical benefits of angiotensin II type 1 (AT1) receptor blockers (ARB) in heart failure (HF) include cardiac anti-remodeling and improved ventricular function. However, the cellular mechanisms underlying the benefits of ARB on ventricular function need to be better clarified. In the present manuscript, we evaluated the effects of AT1 receptor blockade on the net balance of Ca2+ handling proteins in hearts of mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO), which develop sympathetic hyperactivity (SH) induced-HF.Main methods: A cohort of male wild-type (WT) and congenic alpha(2A)/alpha(2C)ARKO mice in a C57BL6/J genetic background (5-7 mo of age) was randomly assigned to receive either placebo or ARB (Losartan, 10 mg/kg for 8wks). Ventricular function (VF) was assessed by echocardiography, and cardiac myocyte width and ventricular fibrosis by a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser(16)-PLN, phospho-Thr(17)-PLN, phosphatase 1 (PP1), Na+-Ca2+ exchanger (NCX), Ca2+/calmodulin-dependent protein kinase 11 (CaMKII) and phospho-Thr(286)-CaMKII were analyzed by Western blot.Key findings: alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis paralleled by decreased SERCA2 and increased phospho-Thr(17)-PLN, CaMKII, phospho-Thr(286)-CaMKII and NCX levels. ARB induced anti-cardiac remodeling effect and improved VF in alpha(2A)/alpha(2C)ARKO associated with increased SERCA2 and phospho-Ser(16)-PLN levels, and SERCA2:NCX ratio. Additionally, ARB decreased phospho-Thr(17)-PLN levels as well as reestablished NCX, CaMKII and phospho-Thr(286)-CaMKII toward WT levels.Significance: Altogether, these data provide new insights on intracellular Ca2+ regulatory mechanisms underlying improved ventricular function by ARB therapy in HF. (c) 2011 Elsevier Inc. All rights reserved.