SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Abstract

Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we analyzed microvascular protective effects of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) on the reperfused heart and examined the role of SERCA in regulating mitochondrial quality control in cardiac microvascular endothelial cells (CMECs). Our data showed that SERCA overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, and improves endothelium-dependent vascular relaxation. In vitro experiments demonstrated that SERCA overexpression improves endothelial viability, barrier integrity, and cytoskeleton assembly in CMECs. Mitochondrial quality control, including mitochondrial fusion, mitophagy, bioenergetics, and biogenesis, were disrupted by I/R injury but were restored by SERCA overexpression. SERCA overexpression also restored mitochondrial quality control by inhibiting calcium overload, inactivating xanthine oxidase (XO), and reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration of exogenous XO or a calcium channel agonist abolished the protective effects of SERCA overexpression on mitochondrial quality control and offset the beneficial effects of SERCA overexpression after cardiac microvascular I/R injury. These findings indicate that SERCA overexpression may be an effective approach to targeting cardiac microvascular I/R injury by regulating calcium/XO/ROS signaling and preserving mitochondrial quality control.

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

“…Studies have shown that endothelial cells are affected earlier and are more sensitive to heart ischemia injury than cardiomyocytes ( Singh et al, 2020 ; Wang et al, 2020a ). Microcirculation injury is one of the most important pathological mechanisms of ischemic injury ( Tan et al, 2020b Wang et al, 2020b ). Myocardial ischemic injury impairs the structure and function of endothelial cells, increases vascular tone, and leads to a decrease in cellular energy metabolism and ATP production ( Bøtker, 2019 ; He et al, 2020 ).…”

Melatonin Attenuates ox‐LDL‐Induced Endothelial Dysfunction by Reducing ER Stress and Inhibiting JNK/Mff Signaling

“…MMP was assessed using the JC-1 mitochondrial membrane potential assay kit (C2006, Beyotime, Shanghai, China) as described in a previous study [42]. HUVECs were collected after treatment with melatonin in the presence of ox-LDL.…”

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“…Intracellular calcium measurements were performed as previously described with minor modifications [ 39 ]. Briefly, H9C2 cells were loaded with 5 μ M Fluo4-AM calcium probe for 30 minutes at 37°C [ 40 ]. Cells were then washed with PBS, and intracellular calcium was observed under a confocal laser scanning microscope (LSM780; Carl Zeiss, Oberkochen, Germany, or TCS SP8; Leica, Wetzlar, Germany) and an Axio Zoom V16 stereo microscope (Carl Zeiss) [ 41 ].…”