Journal of translational medicine · 2025
Peroxynitrite regulates ER stress-mediated Ca2+ flux to mitochondria characterizing cardiac microvascular ischemia-reperfusion injury associated with hyperhomocysteinemia.
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Liu Haipeng, Yu Siyang, Gao Shansong, Liu Xiaoming, Qiu Chengpeng, Wang Ning, Tan Xinyu, Zhao Kaiyang, He Qiuyu, Zhang Wan
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: We demonstrated that ONOO-, generated by the combination of Hcy and Cu2+ during I/R, induces ER stress and the subsequent ER-mitochondria Ca2+ transfer via IP3R-mediated Ca2+ release in CMECs. The cytosolic/mitochondrial Ca2+ oscillations and mitochondrial Ca2+ 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).
CONCLUSIONS: 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--driven ER stress that triggers IP3R-mediated Ca2+ mis-handling, culminating in mitochondrial dysfunction and necroptosis. These data identify IP3R-dependent Ca2+ transfer as a tractable pathway for HHcy-complicated reperfusion injury.
METHODS: 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.
RESULTS: We demonstrated that ONOO-, generated by the combination of Hcy and Cu2+ during I/R, induces ER stress and the subsequent ER-mitochondria Ca2+ transfer via IP3R-mediated Ca2+ release in CMECs. The cytosolic/mitochondrial Ca2+ oscillations and mitochondrial Ca2+ 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).
CONCLUSIONS: 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--driven ER stress that triggers IP3R-mediated Ca2+ mis-handling, culminating in mitochondrial dysfunction and necroptosis. These data identify IP3R-dependent Ca2+ transfer as a tractable pathway for HHcy-complicated reperfusion injury.