Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells.
Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells.
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DOI：
10.1074/jbc.m607391200
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发表时间：
2007-04-13
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影响因子：
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通讯作者：
Nadal-Ginard B
中科院分区：
文献类型：
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作者：
Ellison GM;Torella D;Karakikes I;Purushothaman S;Curcio A;Gasparri C;Indolfi C;Cable NT;Goldspink DF;Nadal-Ginard B
肾上腺素能亢进状态是慢性心力衰竭的一个重要方面。此外，“Takotsubo应激性心肌病”与血浆儿茶酚胺水平升高有关。继发于过量儿茶酚胺暴露的心肌细胞损伤机制以及这种神经体液爆发对心脏干细胞（CSC）的后果尚不清楚。在体内和体外将心肌细胞和CSC暴露于高剂量的异丙肾上腺素（ISO）。雄性Wistar大鼠接受单次注射ISO（5 mg kg-1），并在1、3和6天后处死。与对照组相比，ISO后1天大鼠的LV功能受损，并在3天开始改善。死亡心肌细胞的分数达到高峰后ISO 1天，此后下降。ISO给药导致Ryanodine受体2（RyR 2）过度磷酸化和RyR 2-钙稳定蛋白解离。RyR 2稳定剂JTV 519在体外可阻止ISO诱导的成年心肌细胞死亡。相反，CSCs对急性神经体液超负荷有抵抗力。事实上，CSC表达的β1/β2-肾上腺素受体的补体减少和倒置，并且缺乏RyR 2，这可能解释了它们对ISO损伤的存活。因此，ISO的单次注射通过继发于急性功能失调的RyR 2的Ca 2+渗漏引起弥漫性肌细胞死亡。CSCs对急性肾上腺素能亢进状态的有害作用具有抵抗力，并通过其活化参与对ISO诱导的心肌损伤的反应。后者可能有助于心肌从急性肾上腺素能损伤中迅速恢复的能力。
A hyperadrenergic state is a seminal aspect of chronic heart failure. Also, “Takotsubo stress cardiomyopathy,” is associated with increased plasma catecholamine levels. The mechanisms of myocyte damage secondary to excess catecholamine exposure as well as the consequence of this neurohumoral burst on cardiac stem cells (CSCs) are unknown. Cardiomyocytes and CSCs were exposed to high doses of isoproterenol (ISO), in vivo and in vitro. Male Wistar rats received a single injection of ISO (5 mg kg-1) and were sacrificed 1, 3, and 6 days later. In comparison with controls, LV function was impaired in rats 1 day after ISO and started to improve at 3 days. The fraction of dead myocytes peaked 1 day after ISO and decreased thereafter. ISO administration resulted in significant ryanodine receptor 2 (RyR2) hyperphosphorylation and RyR2-calstabin dissociation. JTV519, a RyR2 stabilizer, prevented the ISO-induced death of adult myocytes in vitro. In contrast, CSCs were resistant to the acute neurohumoral overload. Indeed, CSCs expressed a decreased and inverted complement of β1/β2-adrenoreceptors and absence of RyR2, which may explain their survival to ISO insult. Thus, a single injection of ISO causes diffuse myocyte death through Ca2+ leakage secondary to the acutely dysfunctional RyR2. CSCs are resistant to the noxious effects of an acute hyperadrenergic state and through their activation participate in the response to the ISO-induced myocardial injury. The latter could contribute to the ability of the myocardium to rapidly recover from acute hyperadrenergic damage.