Modulation of Vascular Sarco/Endoplasmic Reticulum Calcium ATPase in Cardiovascular Pathophysiology
Modulation of Vascular Sarco/Endoplasmic Reticulum Calcium ATPase in Cardiovascular Pathophysiology
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DOI：
10.1016/s1054-3589(10)59006-9
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发表时间：
2010-01-01
期刊：
影响因子：
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通讯作者：
Adachi, Takeshi
中科院分区：
文献类型：
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作者：
Adachi, Takeshi
与一氧化氮(NO)生物活性降低相关的内皮功能障碍是动脉粥样硬化或糖尿病等血管疾病的主要特征。硝普钠(SNP)诱导的松弛完全依赖于环鸟苷一磷酸(CGMP)，并在动脉粥样硬化中保存，这表明血管对NO供体的反应是完整的。然而，NO GAS激活血管平滑肌细胞上cGMP依赖和非依赖的信号通路，而与血管疾病相关的氧化应激选择性地损害cGMP非依赖的NO的松弛。肌浆网/内质网钙ATPase(SERCA)通过泵入细胞内钙离子来调节细胞内钙离子水平，是NO的主要cGMP非依赖性靶标。生理水平的反应性氮物种(RNS)S-谷胱甘肽SERCA在Cys674增加其活性，血管疾病中RNS的增加不可逆转地氧化Tyr296-Tyr297上的Cys674或硝酸盐酪氨酸残基，这与功能丧失有关。NO对多种蛋白质的谷胱甘肽氧化修饰可解释氧化还原敏感的cGMP非依赖性作用，靶蛋白对NO的氧化失活可能与心血管疾病的发病机制有关。SERCA的氧化失活还与平滑肌迁移失调、促进血小板聚集和心功能受损有关，这可能与再狭窄、病理性血管生成、血栓形成和心力衰竭有关。分析SERCA的翻译后氧化修饰和保护SERCA的功能可能是治疗与氧化应激相关的心血管疾病的新策略。
Endothelial dysfunction associated with decreased nitric oxide (NO) bioactivity is a major feature of vascular diseases such as atherosclerosis or diabetes. Sodium nitroprusside (SNP)- induced relaxation is entirely dependent on cyclic guanosine monophosphate (cGMP) and preserved in atherosclerosis, suggesting that smooth muscle response to NO donor is intact. However, NO gas activates both cGMP-dependent and - independent signal pathways in vascular smooth muscle cells, and oxidative stress associated with vascular diseases selectively impairs cGMP-independent relaxation to NO. Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), which regulates intracellular Ca2+ levels by pumping Ca2+ into store, is a major cGMP-independent target for NO. Physiological levels of reactive nitrogen species (RNS) S-glutathiolate SERCA at Cys674 to increase its activity, and the augmentation of RNS in vascular diseases irreversibly oxidizes Cys674 or nitrates tyrosine residues at Tyr296-Tyr297, which are associated with loss of function. S-glutathiolation of various proteins by NO can explain redox-sensitive cGMP-independent actions, and oxidative inactivation of target proteins for NO can be associated with the pathogenesis of cardiovascular diseases. Oxidative inactivation of SERCA is also implicated with dysregulation of smooth muscle migration, promotion of platelet aggregation, and impairment of cardiac function, which can be implicated with restenosis, pathological angiogenesis, thrombosis, as well as heart failure. Analysis of posttranslational oxidative modifications of SERCA and the preservation of SERCA function can be novel strategies against cardiovascular diseases associated with oxidative stress.