Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury.
Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury.
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HINT2 通过抑制 MCU 复合物激活对线粒体功能的保护作用减轻心脏微血管缺血再灌注损伤
DOI：
10.1007/s00395-021-00905-4
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发表时间：
2021-12-16
影响因子：
9.5
通讯作者：
Ge J
中科院分区：
文献类型：
--
作者：
Li S;Chen J;Liu M;Chen Y;Wu Y;Li Q;Ma T;Gao J;Xia Y;Fan M;Chen A;Lu D;Su E;Xu F;Chen Z;Qian J;Ge J
目前的证据表明，冠状动脉微循环是预防心脏缺血再灌注（I/R）损伤的关键目标。线粒体钙单向转运蛋白 (MCU) 复合物激活和线粒体钙 ([Ca2+]m) 过载是心血管疾病的潜在机制。据报道，组氨酸三联体核苷酸结合 2 (HINT2) 可通过 MCU 复合物调节 [Ca2+]m，我们之前的工作表明，HINT2 可改善心肌缺血小鼠的心肌细胞存活率并保留心脏功能。本研究旨在探讨 HINT2 对 I/R 损伤中心脏微循环的益处，重点关注线粒体、MCU 复合体和内皮细胞中的 [Ca2+]m 过载。目前的工作表明，HINT2 过表达可能通过促进内皮一氧化氮合酶 (eNOS) 表达和磷酸化，显着减少缺血再灌注损伤小鼠心脏中的无复流区域并改善微血管灌注。微血管屏障功能因再灌注损伤而受到损害，但 HINT2 过表达可通过抑制 Tyr731 的 VE-钙粘蛋白磷酸化并增强 VE-钙粘蛋白/β-连环蛋白相互作用来修复。此外，HINT2 过表达通过抑制血管细胞粘附分子 1 (VCAM-1) 和细胞间粘附分子 1 (ICAM-1) 来抑制炎症反应。遭受氧糖剥夺/复氧 (OGD/R) 损伤的心脏微血管内皮细胞 (CMEC) 发生线粒体裂变，导致线粒体功能障碍和线粒体依赖性细胞凋亡，HINT2 过表达可在很大程度上缓解其影响。其他实验证实，[Ca2+]m 过载是线粒体裂变的启动因素，并且 HINT2 通过直接与 CMEC 中的 MCU 相互作用来调节 MCU 复合物，从而抑制 [Ca2+]m 过载。通过精胺（一种 MCU 激动剂）恢复 [Ca2+]m 过载，消除了 HINT2 对 OGD/R 损伤的 CMEC 和 I/R 损伤的心脏微循环的所有保护作用。总之，本报告证明HINT2过表达抑制MCU复合体-线粒体钙超载-线粒体裂变和凋亡途径，从而减轻心脏微血管缺血再灌注损伤。在线版本包含可在 10.1007/s00395-021-00905-4 获取的补充材料。
Current evidence indicates that coronary microcirculation is a key target for protecting against cardiac ischemia–reperfusion (I/R) injury. Mitochondrial calcium uniporter (MCU) complex activation and mitochondrial calcium ([Ca2+]m) overload are underlying mechanisms involved in cardiovascular disease. Histidine triad nucleotide-binding 2 (HINT2) has been reported to modulate [Ca2+]m via the MCU complex, and our previous work demonstrated that HINT2 improved cardiomyocyte survival and preserved heart function in mice with cardiac ischemia. This study aimed to explore the benefits of HINT2 on cardiac microcirculation in I/R injury with a focus on mitochondria, the MCU complex, and [Ca2+]m overload in endothelial cells. The present work demonstrated that HINT2 overexpression significantly reduced the no-reflow area and improved microvascular perfusion in I/R-injured mouse hearts, potentially by promoting endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Microvascular barrier function was compromised by reperfusion injury, but was repaired by HINT2 overexpression via inhibiting VE-Cadherin phosphorylation at Tyr731 and enhancing the VE-Cadherin/β-Catenin interaction. In addition, HINT2 overexpression inhibited the inflammatory response by suppressing vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mitochondrial fission occurred in cardiac microvascular endothelial cells (CMECs) subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury and resulted in mitochondrial dysfunction and mitochondrion-dependent apoptosis, the effects of which were largely relieved by HINT2 overexpression. Additional experiments confirmed that [Ca2+]m overload was an initiating factor for mitochondrial fission and that HINT2 suppressed [Ca2+]m overload via modulation of the MCU complex through directly interacting with MCU in CMECs. Regaining [Ca2+]m overload by spermine, an MCU agonist, abolished all the protective effects of HINT2 on OGD/R-injured CMECs and I/R-injured cardiac microcirculation. In conclusion, the present report demonstrated that HINT2 overexpression inhibited MCU complex-mitochondrial calcium overload-mitochondrial fission and apoptosis pathway, and thereby attenuated cardiac microvascular ischemia–reperfusion injury. The online version contains supplementary material available at 10.1007/s00395-021-00905-4.
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