Dataset Information

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

ABSTRACT: Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of microvascular I/R injury.

SUBMITTER: Zhou H

PROVIDER: S-EPMC7023463 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

Zhou Hao H Zhou Hao H Toan Sam S

Biomolecules 20200105 1

Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell ty ...[more]

PMID: 31948043

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Project description: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.

Project description:Activating transcription factor 3 (ATF3) has been confirmed to be responsive to oxidative stress and to negatively regulate the activity of Toll-like receptor 4 (TLR4). However, the effect of ATF3 on cardiac microvascular ischemia/reperfusion (I/R) injury remains unknown. The GEO2R online tool was employed to obtain differentially expressed genes GSE4105 and GSE122020, in two rat I/R injury microarray datasets. We established a rat myocardial I/R model in vivo, and also generated an in vitro hypoxia/reoxygenation (H/R) model of cardiomyoblast H9c2 cells. Overexpression of ATF3 was achieved by adenoviral-mediated gene transfer (Ad-ATF3). Rats were randomly divided into four groups: sham, I/R, I/R + Ad-Lacz (as a control), and I/R + Ad-ATF3. ELISA, CCK-8, DCFH-DA probe, qRT-PCR and Western blotting were used to determine the expression of ATF3, oxidative indices, cellular injury and TLR4/NF-κB pathway-associated proteins. Transmission electron microscopy, immunohistochemistry and immunofluorescence were used to detect the leukocyte infiltration and the alteration of microvascular morphology and function in vivo. Echocardiographic and hemodynamic data were also obtained. Bioinformatics analysis revealed that ATF3 was upregulated in I/R myocardia in two independent rat myocardial I/R models. Cardiac microvascular I/R injury included leukocyte infiltration, microvascular integrity disruption, and microvascular perfusion defect, which eventually resulted in the deterioration of hemodynamic parameters and heart function. Ad-ATF3 significantly restored microvascular function, increased cardiac microvascular perfusion, and improved hemodynamic parameters and heart function. Mechanistically, Ad-ATF3 ameliorated oxidative stress, inhibited TLR4/NF-κB pathway activation and down-regulated the expression of downstream proinflammatory cytokines in I/R myocardium in vivo and in H/R H9c2 cells in vitro. ATF3 overexpression protects against cardiac microvascular I/R injury in part by inhibiting the TLR4/NF-κB pathway and oxidative stress.

Project description:Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis.

Dataset Information

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

Publications

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

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