SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways
SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways
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DOI：
10.1016/j.redox.2020.101659
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Liang, Jianqiu
中科院分区：
文献类型：
--
作者：
Li, Chen;Ma, Qinghui;Liang, Jianqiu
微血管系统内的内皮细胞特别容易受到心肌缺血/再灌注(I/R)损伤的有害影响，这种敏感性部分是由细胞内钙信号调节失调所介导的。肌浆/内质网钙-ATPase(SERCA)负责将胞浆中的钙循环回内质网。本研究旨在探讨SERCA对心脏I/R损伤微循环的保护作用及其机制。我们的数据显示，SERCA的过度表达显著减少了I/R诱导的管腔狭窄和血管壁水肿，这可能是通过正常化eNOS和ET-1的比率实现的。SERCA过表达可通过转录抑制黏附因子的表达，逆转I/R所致的红细胞微血管形态改变。此外，SERCA维持的内皮屏障完整性降低了炎症细胞渗入心肌的可能性。此外，我们还发现，SERCA过表达可减轻心肌微血管内皮细胞内钙超载，抑制线粒体钙单一转运体(MCU)的表达，阻止线粒体通透性转换孔(MPTP)的异常开放。有趣的是，钙激活剂或MCU激动剂在体外诱导内皮细胞坏死性下垂，从而在体内消除了SERCA对再灌注心脏组织的微血管保护作用。总之，通过使用基因传递策略在体外和体内特异性地靶向SERCA，我们发现了一条潜在的新途径，SERCA的过度表达通过依赖于钙/MCU/坏死性下垂途径来保护微循环免受心脏I/R损伤。在制定针对心脏微血管I/R损伤的治疗干预的药理学策略时，应考虑这些发现。
Endothelial cells lining the microvasculature are particularly vulnerable to the deleterious effects of cardiac ischemia/reperfusion (I/R) injury, a susceptibility that is partially mediated by dysregulated intracellular calcium signals. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) functions to recycle calcium from the cytosol back to the endoplasmic reticulum. The purpose of this study is to explore the roles and mechanisms of SERCA in protecting microcirculation against cardiac I/R injury. Our data showed that overexpression of SERCA significantly reduced I/R-induced luminal stenosis and vascular wall edema, possibly through normalization of the ratio between eNOS and ET-1. I/R-induced erythrocyte morphological changes in micro-vessels could be reversed by SERCA overexpression through transcriptional inhibition of the expression of adhesive factors. In addition, SERCA-sustained endothelial barrier integrity reduced the likelihood of inflammatory cells infiltrating the myocardium. Furthermore, we found that SERCA overexpression attenuated intracellular calcium overload, suppressed mitochondrial calcium uniporter (MCU) expression, and prevented the abnormal opening of mitochondrial permeability transition pores (mPTP) in I/R-treated cardiac microvascular endothelial cells (CMECs). Interestingly, the administration of calcium activator or MCU agonist induced endothelial necroptosis in vitro and thus abolished the microvascular protection afforded by SERCA in reperfused heart tissue in vivo. In conclusion, by using gene delivery strategies to specifically target SERCA in vitro and in vivo, we identify a potential novel pathway by which SERCA overexpression protects microcirculation against cardiac I/R injury in a manner dependent on the calcium/MCU/necroptosis pathway. These findings should be taken into consideration in the development of pharmacological strategies for therapeutic interventions against cardiac microvascular I/R injury.