Peroxynitrite regulates ER stress-mediated Ca2+ flux to mitochondria characterizing cardiac microvascular ischemia–reperfusion injury associated with hyperhomocysteinemia

作者：Haipeng Liu, Siyang Yu, Shansong Gao, Xiaoming Liu, Chengpeng Qiu, Ning Wang, Xinyu Tan, Kaiyang Zhao, Qian He, Wan Zhang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07263-y · 被引用次数：7 · 研究领域：Mitochondrial Function and Pathology、Folate and B Vitamins Research、Nitric Oxide and Endothelin Effects

Homocysteine (Hcy) is not only associated with the development of chronic cardiovascular diseases like atherosclerosis, but may also participate in the acute cardiovascular events. However, the exact mechanism of the latter remains elusive. The present study aims to further investigate the mechanism of cardiac microvascular endothelial cells (CMECs) death after I/R induction in the presence of Hcy and explore new therapeutic strategies. By generating the hypoxia/reoxygenation (H/R) human cardiac microvascular endothelial cell (HCMEC) model and the I/R models in rats with hyperhomocysteinemia (HHcy), the mechanisms of endothelial cell injury associated with HHcy were investigated. We demonstrated that ONOO − , generated by the combination of Hcy and Cu 2+ during I/R, induces ER stress and the subsequent ER-mitochondria Ca 2+ transfer via IP3R-mediated Ca 2+ release in CMECs. The cytosolic/mitochondrial Ca 2+ oscillations and mitochondrial Ca 2+ overload promote mROS generation, provoke LMP, and ultimately drive CMEC necroptosis. Our study further demonstrates the IP3R inhibitor 2-APB (5 mg/kg) significantly reduced infarct size by 29.14%, and improved cardiac function in HHcy rats (HHcyR), as evidenced by increased LVEF (35.71% → 55.32%), elevated LVFS (31.44% → 48.54%), and reduced LVEDd (6.98 mm → 5.80 mm). Altogether, our results reveal the pathological role of Hcy in acute cardiovascular events. We show that HHcy aggravates cardiac microvascular I/R injury via ONOO − -driv...