Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure
Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure
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DOI：
10.1172/jci31060
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Nakayama, Hiroyuki;Chen, Xiongwen;Molkentin, Jeffery D.
心力衰竭时心肌细胞的损失被认为主要是通过凋亡过程发生的。在这里，我们表明心力衰竭也可以通过与Ca2+超载相关的心肌细胞坏死而沉淀。肌上皮l型Ca2+通道（LTCC）活性增强的诱导转基因小鼠表现出进行性肌细胞坏死，导致泵功能障碍和过早死亡，急性刺激p -肾上腺素能受体可显著增强这一效应。LTCC阻滞剂或p -肾上腺素能受体拮抗剂均可预防Ca2+流入引起的细胞坏死和心肌病，这表明p -肾上腺素能受体功能、Ca2+处理和通过坏死细胞损失导致的心力衰竭进展之间存在密切关系。在机制上，亲环蛋白D（线粒体通透性过渡孔的调节因子，支持坏死）的丧失可以阻断Ca2+流入诱导的心肌细胞坏死、心力衰竭和异丙肾上腺素诱导的过早死亡。相反，抗凋亡因子Bcl-2的过度表达在减轻与过量Ca2+内流和急性β -肾上腺素能受体刺激相关的心力衰竭和死亡方面无效。这种线粒体和坏死依赖性心力衰竭的模式也在其他疾病小鼠模型中观察到，这支持了心力衰竭是一种多效性疾病的概念，不仅涉及细胞凋亡，还涉及与Ca2+处理和p -肾上腺素能受体信号失调相关的肌细胞坏死损失。
Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of P-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or P-adrenergic receptor antagonists, demonstrating a proximal relationship among P-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and P-adrenergic receptor signaling.