Early impairment of calcium handling and altered expression of junctin in hearts of mice overexpressing the β1-adrenergic receptor
Early impairment of calcium handling and altered expression of junctin in hearts of mice overexpressing the β1-adrenergic receptor
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DOI：
10.1096/fj.01-0107fje
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发表时间：
2001-10-01
期刊：
影响因子：
4.8
通讯作者：
Hein, L
中科院分区：
文献类型：
--
作者：
Engelhardt, S;Boknik, P;Hein, L
心脏 β (1)-肾上腺素能受体的慢性刺激会导致心力衰竭患者和动物模型的疾病进展和死亡率。为了寻找体内肾上腺素能损害心脏功能的机制，我们研究了心脏特异性过度表达β(1)-肾上腺素能受体的转基因小鼠。心脏过度表达 β(1)-肾上腺素能受体的转基因小鼠从 4 个月大时开始表现出进行性左心室纤维化。左心室导管检查显示 2 个月大时收缩性和舒张性适度增强，随后这两个参数出现进行性功能障碍，最终出现心力衰竭。当内源性儿茶酚胺的作用被β受体拮抗剂普萘洛尔阻断时，2个月大的β(1)受体转基因小鼠的最大收缩率(dp/dt(max))和最大舒张率(dp/dt(min))显着减弱。与非转基因同窝动物相比，来自这些动物的分离的心肌细胞表现出明显改变的钙瞬变，并且细胞内钙瞬变显着延长。我们通过 RNase 保护测定和免疫印迹测定了参与钙处理的肌浆网蛋白的表达。尽管钙螯合蛋白、三联蛋白和受磷蛋白的表达没有改变，但我们观察到β（1）受体转基因小鼠中的连接蛋白丰度逐渐减少（P
Chronic stimulation of cardiac beta (1)-adrenergic receptors contributes to disease progression and mortality in patients and animal models of heart failure. To search for the mechanism of adrenergic impairment of cardiac function in vivo, we studied transgenic mice with cardiac-specific overexpression of beta (1)-adrenergic receptors. Transgenic mice with cardiac overexpression of beta (1)-adrenergic receptors showed progressive left ventricular fibrosis starting at 4 months of age. Left ventricular catheterization revealed a modest enhancement of contractility and relaxation at 2 months of age, followed by progressive dysfunction in both parameters and ultimately cardiac failure. When the effects of endogenous catecholamines were blocked by the beta -receptor antagonist propranolol, maximal rate of contractility (dp/dt(max)) and maximal rate of relaxation (dp/dt(min)) were significantly blunted in 2-month-old beta (1)-receptor transgenic mice. Isolated cardiomyocytes from these animals displayed markedly altered calcium transients with significant prolongation of the intracellular calcium transient compared with nontransgenic littermates. We determined the expression of sarcoplasmic reticulum proteins involved in calcium handling by RNase protection assay and by immunoblotting. Although the expression of calsequestrin, triadin, and phospholamban was not altered, we observed a progressive decrease in junctin abundance in beta (1)-receptor transgenic mice (P