SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways

Abstract

Endothelial cells lining the microvasculature are particularly vulnerable to the deleterious effects of cardiac ischemia/reperfusion (I/R) injury, a susceptibility that is partially mediated by dysregulated intracellular calcium signals. Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) functions to recycle calcium from the cytosol back to the endoplasmic reticulum. The purpose of this study is to explore the roles and mechanisms of SERCA in protecting microcirculation against cardiac I/R injury. Our data showed that overexpression of SERCA significantly reduced I/R-induced luminal stenosis and vascular wall edema, possibly through normalization of the ratio between eNOS and ET-1. I/R-induced erythrocyte morphological changes in micro-vessels could be reversed by SERCA overexpression through transcriptional inhibition of the expression of adhesive factors. In addition, SERCA-sustained endothelial barrier integrity reduced the likelihood of inflammatory cells infiltrating the myocardium. Furthermore, we found that SERCA overexpression attenuated intracellular calcium overload, suppressed mitochondrial calcium uniporter (MCU) expression, and prevented the abnormal opening of mitochondrial permeability transition pores (mPTP) in I/R-treated cardiac microvascular endothelial cells (CMECs). Interestingly, the administration of calcium activator or MCU agonist induced endothelial necroptosis in vitro and thus abolished the microvascular protection afforded by SERCA in reperfused heart tissue in vivo . In conclusion, by using gene delivery strategies to specifically target SERCA in vitro and in vivo , we identify a potential novel pathway by which SERCA overexpression protects microcirculation against cardiac I/R injury in a manner dependent on the calcium/MCU/necroptosis pathway. These findings should be taken into consideration in the development of pharmacological strategies for therapeutic interventions against cardiac microvascular I/R injury.

[Retracted] Tongyang Huoxue Decoction (TYHX) Ameliorating Hypoxia/Reoxygenation‐Induced Disequilibrium of Calcium Homeostasis and Redox Imbalance via Regulating Mitochondrial Quality Control in Sinoatrial Node Cells

“…The activity and expression of SERCA are essential for maintaining a baseline calcium release or resting intracellular calcium. Various studies have reported the cardioprotective effects of SERCA [ 12 , 34 , 35 ]. The decreased expression of SERCA can mediate endothelial cell necrosis in ischemia-reperfusion.…”

“…As the main site of ROS production and the first target of ROS attack, excessive ROS production can lead to dysfunction of mitochondrial respiratory electron-transport chain and further affect the balance of redox in cells [ 10 ]. Therefore, under the stimulation of hypoxia, inflammation, and high glucose, it will lead to excessive production of ROS and induce structural and functional abnormalities of mitochondria, including imbalance of mitochondrial energy metabolism, reduction of mitochondrial biosynthesis, and abnormal opening of mitochondrial membrane permeability transition pore (mPTP) [ 11 , 12 ].…”

RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK‐Parkin‐Mitophagy in Cardiac Remodelling after Myocardial Infarction

“…Reactive Oxygen Species (ROS) Assays. ROS were measured after staining with dihydroethidium (DHE; Invitrogen, USA) [31]. The fluorescence was observed under microscopes and further analysed by flow cytometry.…”

Transcriptomic‐based toxicological investigations of ethanol to human umbilical vein endothelial cells

“…It was confirmed that both concentrations of ethanol downregulated key genes related with calcium signaling pathway (Figure 6). Interestingly, previous studies also found that dysfunction in calcium signaling is involved in endothelial dysfunction (Cheriyan et al, 2020; Li et al, 2020; Wang et al, 2020). Key genes related with PI3K‐Akt signaling pathway were also downregulated by ethanol, but 50‐mM ethanol appeared to be more effectively compared with 5‐mM ethanol (Figure 7).…”