RETRACTED: Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

Abstract

Our previous research has shown that type-2a Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) undergoes posttranscriptional oxidative modifications in cardiac microvascular endothelial cells (CMECs) in the context of excessive cardiac oxidative injury. However, whether SERCA2a inactivity induces cytosolic Ca2+ imbalance in mitochondrial homeostasis is far from clear. Mitofusin2 (Mfn2) is well known as an important protein involved in endoplasmic reticulum (ER)/mitochondrial Ca2+ tethering and the regulation of mitochondrial quality. Therefore, the aim of our study was to elucidate the specific mechanism of SERCA2a-mediated Ca2+ overload in the mitochondria via Mfn2 tethering and the survival rate of the heart under conditions of cardiac microvascular ischemic injury. In vitro, CMECs extracted from mice were subjected to 6 h of hypoxic injury to mimic ischemic heart injury. C57-WT and Mfn2KO mice were subjected to a 1 h ischemia procedure via ligation of the left anterior descending branch to establish an in vivo cardiac ischemic injury model. TTC staining, immunohistochemistry and echocardiography were used to assess the myocardial infarct size, microvascular damage, and heart function. In vitro, ischemic injury induced irreversible oxidative modification of SERCA2a, including sulfonylation at cysteine 674 and nitration at tyrosine 294/295, and inactivation of SERCA2a, which initiated calcium overload. In addition, ischemic injury-triggered [Ca2+]c overload and subsequent [Ca2+]m overload led to mPTP opening and ΔΨm dissipation compared with the control. Furthermore, ablation of Mfn2 alleviated SERCA2a-induced mitochondrial calcium overload and subsequent mito-apoptosis in the context of CMEC hypoxic injury. In vivo, compared with that in wild-type mice, the myocardial infarct size in Mfn2KO mice was significantly decreased. In addition, the findings revealed that Mfn2KO mice had better heart contractile function, decreased myocardial infarction indicators, and improved mitochondrial morphology. Taken together, the results of our study suggested that SERCA2a-dependent [Ca2+]c overload led to mitochondrial dysfunction and activation of Mfn2-mediated [Ca2+]m overload. Overexpression of SERCA2a or ablation of Mfn2 expression mitigated mitochondrial morphological and functional damage by modifying the SERCA2a/Ca2+-Mfn2 pathway. Overall, these pathways are promising therapeutic targets for acute cardiac microvascular ischemic injury.

Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia–reperfusion injury

“…However, the pathological role of calcium overload in microvascular reperfusion injury is a neglected target for cardioprotection. Limited evidence has proven that the restriction of endothelial mitochondrial calcium ([Ca 2+ ] m ) influx exerted benefits on cardiac microcirculation, as evidenced by enhanced microvascular perfusion, reduced microvascular obstruction, inhibited inflammatory cell infiltration, and decreased infarction size in a mouse cardiac I/R model, and the potentially involved mechanisms were largely attributed to mitigated mitochondrial morphological and functional damage [27,47]. [Ca 2+ ] m influx is primarily mediated by the mitochondrial calcium uniporter (MCU) complex, which mainly consists of four MCU subunits and essential MCU regulators (EMREs) [2,46].…”

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

“…The cardiac microcirculation is composed of a monolayer of endothelial cells, which are known as cardiac microvascular endothelial cells (CMECs). Ample studies have identified CMEC dysfunction or death as a pathological feature of cardiac microvascular I/R injury [ 42 , 43 ]; thus, we assessed the effects of empagliflozin on endothelial cells. CMECs synthesize and release nitric oxide via eNOS, thereby promoting vascular relaxation.…”

Inhibition of Myocardial Cell Apoptosis Is Important Mechanism for Ginsenoside in the Limitation of Myocardial Ischemia/Reperfusion Injury

“…The lack of ATP reduces the activity of sodium–potassium pumps on the membrane, leading to calcium overload ( Zhang et al, 2020 ). Calcium overload induces arrhythmias ( Tribulova et al, 2016 ; Sugiyama et al, 2021 ), mitochondrial dysfunction ( Tian and Zhang, 2021 ), and MC apoptosis ( Gao et al, 2021 ). The recommended therapy of MI is reperfusion, namely, restoration of blood flow to ischemic areas ( Jneid et al, 2017 ).…”