β-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic Gsα mouse
β-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic Gsα mouse
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DOI：
10.1172/jci7418
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发表时间：
1999-09-01
影响因子：
15.9
通讯作者：
Vatner, SF
中科院分区：
文献类型：
--
作者：
Asai, K;Yang, GP;Vatner, SF
心脏G（s α）过表达的转基因（TG）小鼠对交感神经刺激表现出增强的变力性和变时性反应，但随着年龄的增长会发生心肌病。我们检验了一个假设，即Gs α过表达的TG小鼠的心肌病可以通过慢性β-肾上腺素能受体（β-AR）阻断来避免。TG小鼠和年龄匹配的野生型同窝小鼠用β-AR阻断剂普萘洛尔治疗6-7个月，开始于心肌病正在发展但尚未严重到足以诱导显著心脏抑制的时间（9.5月龄），结束于心脏抑制和心肌病明显表现的时间（16月龄）。普萘洛尔治疗，可以诱导心脏抑制在正常的心脏，实际上防止心脏扩张和抑郁的左心室功能的特点，老年TG小鼠，并消除过早死亡。普萘洛尔也防止了心肌细胞横截面积的增加和心肌纤维化。肌细胞凋亡，已经明显在3个月大的TG小鼠，实际上消除了慢性普萘洛尔。这项研究表明，长期慢性交感神经刺激是有害的，会导致心肌病。相反，PAR阻断在这种情况下是有益的，可以防止心肌病的发展。
Transgenic (TG) mice with cardiac G(s alpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with Gs alpha overexpression could be averted with chronic beta-adrenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type littermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of older TG mice, and abolished premature mortality. Propranolol also prevented the increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 3-month-old TG mice, was actually eliminated by chronic propranolol. This study indicates that chronic sympathetic stimulation over an extended period is deleterious and results in cardiomyopathy. Conversely, PAR blockade is salutary in this situation and can prevent the development of cardiomyopathy.