MCUb Induction Protects the Heart From Postischemic Remodeling

Huo, Jiuzhou; Lü, Shan; Kwong, Jennifer Q.; Bround, Michael J.; Grimes, Kelly M.; Sargent, Michelle A.; Brown, Milton E.; Davis, Michael; Bers, Donald M.; Molkentin, Jeffery D.

doi:10.1161/circresaha.119.316369

Cited by 52 publications

(47 citation statements)

References 42 publications

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“…Restraining [Ca 2+ ] m influx via the upregulation of MICU1 protected the heart from I/R injury [3,50]. MCUb was not expressed at baseline, but was upregulated when sensing calcium elevation in the cytoplasm [21]. MCUb overexpression reduced mPTP opening and decreased infarct size following IR injury [21,26].…”

Section: Discussionmentioning

confidence: 98%

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

Chen

Liu

et al. 2021

Basic Res Cardiol

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Current evidence indicates that coronary microcirculation is a key target for protecting against cardiac ischemia–reperfusion (I/R) injury. Mitochondrial calcium uniporter (MCU) complex activation and mitochondrial calcium ([Ca2+]m) overload are underlying mechanisms involved in cardiovascular disease. Histidine triad nucleotide-binding 2 (HINT2) has been reported to modulate [Ca2+]m via the MCU complex, and our previous work demonstrated that HINT2 improved cardiomyocyte survival and preserved heart function in mice with cardiac ischemia. This study aimed to explore the benefits of HINT2 on cardiac microcirculation in I/R injury with a focus on mitochondria, the MCU complex, and [Ca2+]m overload in endothelial cells. The present work demonstrated that HINT2 overexpression significantly reduced the no-reflow area and improved microvascular perfusion in I/R-injured mouse hearts, potentially by promoting endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Microvascular barrier function was compromised by reperfusion injury, but was repaired by HINT2 overexpression via inhibiting VE-Cadherin phosphorylation at Tyr731 and enhancing the VE-Cadherin/β-Catenin interaction. In addition, HINT2 overexpression inhibited the inflammatory response by suppressing vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mitochondrial fission occurred in cardiac microvascular endothelial cells (CMECs) subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury and resulted in mitochondrial dysfunction and mitochondrion-dependent apoptosis, the effects of which were largely relieved by HINT2 overexpression. Additional experiments confirmed that [Ca2+]m overload was an initiating factor for mitochondrial fission and that HINT2 suppressed [Ca2+]m overload via modulation of the MCU complex through directly interacting with MCU in CMECs. Regaining [Ca2+]m overload by spermine, an MCU agonist, abolished all the protective effects of HINT2 on OGD/R-injured CMECs and I/R-injured cardiac microcirculation. In conclusion, the present report demonstrated that HINT2 overexpression inhibited MCU complex-mitochondrial calcium overload-mitochondrial fission and apoptosis pathway, and thereby attenuated cardiac microvascular ischemia–reperfusion injury.

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Section: Discussionmentioning

confidence: 98%

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

Chen

Liu

et al. 2021

Basic Res Cardiol

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“…MCUB is a necessary part of a protective response against mitochondrial Ca 2+ overload during cardiac injury and ischemia 87 . Mcub -/- mice displayed increased cardiac remodelling and ischemic injury as a result of increased mitochondrial Ca 2+ uptake 88 . Although more research is required to fully understand the role of MCUB in severe COVID-19 pathogenesis, a decreased level of serum calcium has been suggested as a biomarker for increased COVID-19 severity and ARDS 89 .…”

Section: Discussionmentioning

confidence: 98%

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Taylor¹,

Das²,

Pearson³

et al. 2020

Preprint

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BACKGROUND Epidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors that impact differential host responses to SARS-CoV-2, resulting in the development of severe COVID-19, is important in gaining greater understanding into the biological mechanisms underpinning life-threatening responses to the virus. These insights could be used in the identification of high-risk individuals and for the development of treatment strategies for these patients. METHODS As of June 6, 2020, there were 976 patients who tested positive for COVID-19 and were hospitalized, indicating they had a severe response to SARS-CoV-2. There were however too few patients with a mild form of COVID-19 to use this cohort as our control population. Instead we used similar control criteria to our previous study looking at shared genetic risk factors between severe COVID-19 and sepsis, selecting controls who had not developed sepsis despite having maximum co-morbidity risk and exposure to sepsis-causing pathogens. RESULTS Using a combinatorial (high-order epistasis) analysis approach, we identified 68 protein-coding genes that were highly associated with severe COVID-19. At the time of analysis, nine of these genes have been linked to differential response to SARS-CoV-2. We also found many novel targets that are involved in key biological pathways associated with the development of severe COVID-19, including production of pro-inflammatory cytokines, endothelial cell dysfunction, lipid droplets, neurodegeneration and viral susceptibility factors. CONCLUSION The variants we found in genes relating to immune response pathways and cytokine production cascades, were in equal proportions across all severe COVID-19 patients, regardless of their co-morbidities. This suggests that such variants are not associated with any specific co-morbidity, but are common amongst patients who develop severe COVID-19. Among the 68 severe COVID-19 risk-associated genes, we found several druggable protein targets and pathways. Nine are targeted by drugs that have reached at least Phase I clinical trials, and a further eight have active chemical starting points for novel drug development. Several of these targets were particularly enriched in specific co-morbidities, providing insights into shared pathological mechanisms underlying both the development of severe COVID-19, ARDS and these predisposing co-morbidities. We can use these insights to identify patients who are at greatest risk of contracting severe COVID-19 and develop targeted therapeutic strategies for them, with the aim of improving disease burden and survival rates.

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“…Using mice with cardiomyocyte-specific overexpression or deletion of MCUB, Huo et al . 56 showed that MCUB is inducible and limits mitochondrial Ca 2+ influx after IR, preventing mitochondrial permeability transition pore (mPTP) opening and protecting the myocardium. Interestingly, hindlimb remote ischemic preconditioning increased MCUB expression in the heart and decreased mitochondrial Ca 2+ uptake.…”

Section: Powering the Heart—mitochondria And Metabolismmentioning

confidence: 99%

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart

Davidson

Padró

Bollini

et al. 2021

Cardiovascular Research

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We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches such as a glycocalyx mimetic were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to cell communication, in particular the relevance of extracellular vesicles such as exosomes, which transport proteins, lipids, non-coding RNAs and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.

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MCUb Induction Protects the Heart From Postischemic Remodeling

Cited by 52 publications

References 42 publications

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

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

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart

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