Since its recognition in December 2019, covid-19 has rapidly spread globally causing a pandemic. Pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease are associated with a greater severity and higher fatality rate of covid-19. Furthermore, covid-19 contributes to cardiovascular complications, including acute myocardial injury as a result of acute coronary syndrome, myocarditis, stress-cardiomyopathy, arrhythmias, cardiogenic shock, and cardiac arrest. The cardiovascular interactions of covid-19 have similarities to that of severe acute respiratory syndrome, Middle East respiratory syndrome and influenza. Specific cardiovascular considerations are also necessary in supportive treatment with anticoagulation, the continued use of renin-angiotensin-aldosterone system inhibitors, arrhythmia monitoring, immunosuppression or modulation, and mechanical circulatory support.

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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.

The death of cardiomyocytes either through apoptosis or necroptosis is the pathological feature of cardiac ischemia-reperfusion (I/R) injury. Phosphoglycerate mutase 5 (PGAM5), a mitochondrially-localized serine/threonine-protein phosphatase, functions as a novel inducer of necroptosis. However, intense debate exists regarding the effect of PGAM5 on I/R-related cardiomyocyte death. Using cardiac-specific PGAM5 knockout (PGAM5 CKO ) mice, we comprehensively investigated the precise contribution and molecular mechanism of PGAM5 in cardiomyocyte death. Our data showed that both PGAM5 transcription and expression were upregulated in reperfused myocardium. Genetic ablation of PGAM5 suppressed I/R-mediated necroptosis but failed to prevent apoptosis activation, a result that went along with improved heart function and decreased inflammation response. Regardless of PGAM5 status, mitophagy-related cell death was not apparent following I/R. Under physiological conditions, PGAM5 overexpression in primary cardiomyocytes was sufficient to induce cardiomyocyte necroptosis rather than apoptosis. At the sub-cellular levels, PGAM5 deficiency increased mitochondrial DNA copy number and transcript levels, normalized mitochondrial respiration, repressed mitochondrial ROS production, and prevented abnormal mPTP opening upon I/R. Molecular investigation demonstrated that PGAM5 deletion interrupted I/R-mediated Drp S637 dephosphorylation but failed to abolish I/R-induce Drp1 S616 phosphorylation, resulting in partial inhibition of mitochondrial fission. In addition, declining Mfn2 and OPA1 levels were restored in PGAM5 CKO cardiomyocytes following I/R. Nevertheless, PGAM5 depletion did not rescue suppressed mitophagy upon I/R injury. In conclusion, our results provide an insight into the specific role and working mechanism of PGAM5 in driving cardiomyocyte necroptosis through imposing mitochondrial quality control in cardiac I/R injury.

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) regulates cell death. We sought to determine whether DNA-PKcs played a role in the tubular damage that occurs during acute kidney injury (AKI) induced by LPS injection (to mimic sepsis), cisplatin administration, or renal ischemia/reperfusion injury. Although DNA-PKcs normally localizes to the nucleus, we detected cytoplasmic DNA-PKcs in mouse kidney tissues and urinary sediments of human patients with septic AKI. Increased cytoplasmic amounts of DNA-PKcs correlated with renal dysfunction. Tubule cell–specific DNA-PKcs deletion attenuated AKI-mediated tubular cell death and changes in the abundance of various proteins with mitochondrial functions or roles in apoptotic pathways. DNA-PKcs interacted with Fis1 and phosphorylated it at Thr 34 in its TQ motif, which increased the affinity of Fis1 for Drp1 and induced mitochondrial fragmentation. Knockin mice expressing a nonphosphorylatable T34A mutant exhibited improved renal function and histological features and reduced mitochondrial fragmentation upon induction of AKI. Phosphorylation of Thr 34 in Fis1 was detectable in urinary sediments of human patients with septic AKI and correlated with renal dysfunction. Our findings provide insight into the role of cytoplasmic DNA-PKcs and phosphorylated Fis1 in AKI development.