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.

Statin treatment reduces cardiovascular risk. However, individuals with well-controlled low-density lipoprotein (LDL) levels may remain at increased risk owing to persistent high triglycerides and low high-density lipoprotein cholesterol. Because resveratrol promotes glucose metabolism and mitigates cardiovascular disorders, we explored its mechanism of protective action on high-fat-induced endothelial dysfunction. Human umbilical venous endothelial cells were treated with oxidized LDL (ox-LDL) in vitro. Endothelial function, cell survival, proliferation, migration, and oxidative stress were analyzed through western blots, quantitative polymerase chain reaction, ELISA, and immunofluorescence. ox-LDL induced endothelial cell apoptosis, proliferation arrest, and mobilization inhibition, all of which resveratrol reduced. ox-LDL suppressed the activities of mitochondrial respiration complex I and III and reduced levels of intracellular antioxidative enzymes, resulting in reactive oxygen species overproduction and mitochondrial dysfunction. Resveratrol treatment upregulated Bnip3-related mitophagy and prevented ox-LDL-mediated mitochondrial respiration complexes inactivation, sustaining mitochondrial membrane potential and favoring endothelial cell survival. We found that resveratrol enhanced Bnip3 transcription through hypoxia-inducible factor 1 (HIF1) and 5 AMP-activated protein kinase (AMPK). Inhibition of AMPK and HIF1 abolished resveratrol-mediated protection of mitochondrial redox balance and endothelial viability. Together, these data demonstrate resveratrol reduces hyperlipemiarelated endothelial damage by preserving mitochondrial homeostasis.

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