New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury

Wang, Jin; Toan, Sam; Zhou, Hao

doi:10.1007/s10456-020-09720-2

Cited by 254 publications

(175 citation statements)

References 209 publications

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“…Damaged microcirculation is associated with endothelial cell hyper-permeability 12 and inflammatory cell infiltration into the myocardium. 29 Using double immunofluorescence, we observed that the numbers of Gr1-positive neutrophils were increased in I/R-treated mice hearts relative to sham mice ( Figures 1 H and 1I).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that mitochondria play an important role in sustaining microvascular structure and function. 12 , 31 To understand the role of SERCA in mitochondrial homeostasis, we analyzed mitochondrial fusion and mitophagy. Compared with the control group, sI/R substantially suppressed the mRNA expression of Mfn2 and Opa1 ( Figures 3 A and 3B), suggesting that mitochondrial fusion was inhibited by sI/R injury.…”

Section: Resultsmentioning

confidence: 99%

“… 10 , 11 Multiple mechanisms are involved in the pathophysiological alterations of cardiac microvascular endothelial cells (CMECs) dysfunction in cardiac I/R injury, including oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum (ER) damage, and NO regulatory system impairment. 12 , 13 , 14 Among these pathological factors, mitochondrial dysfunction and calcium overload have been proposed as the critical mechanisms responsible for the I/R-induced endothelial damage. 15 , 16 First, although endothelial cells rely mainly on mitochondria-independent glycolysis for their energy demands, regardless of the high oxygen abundance in the vascular compartment, mitochondrial quality-control damage (including mitochondrial morphological alterations and mitochondrial function reduction) is closely associated with endothelial cell oxidative stress and apoptosis activation.…”

Section: Introductionmentioning

confidence: 99%

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SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Tan

Mui

Toan

et al. 2020

Molecular Therapy - Nucleic Acids

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119

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Tan

Mui

Toan

et al. 2020

Molecular Therapy - Nucleic Acids

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119

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“…Compared with these organs, endothelium is more vulnerable to hyperlipemia-triggered pathological injuries, including oxidative stress, metabolic disorder, cell senescence, and fibrosis (Wang et al, 2020a;Zhou and Toan, 2020). Additionally, owing to direct contact with blood, endothelium responds to blood composition alterations (Heusch, 2019;Wang et al, 2020b). Accordingly, hyperlipemia-mediated damage is likely to be seen in endothelium (Korbel et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction

Tan

et al. 2020

Front. Cell Dev. Biol.

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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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“…Increased levels Bax and decreased levels Bcl-2 are hallmarks of mitochondrial apoptosis activation and have been noted in the reperfused heart tissues (Yang et al, 2019b). Inhibition of mitochondria-related oxidative stress, mitochondria-induced intracellular calcium overload, and mitochondria-triggered cardiomyocyte apoptosis partially alleviates myocardial damage after cardiac I/R injury (Chen et al, 2019b;Wang et al, 2020b;.…”

Section: Introductionmentioning

confidence: 99%

AMPKα2 Overexpression Reduces Cardiomyocyte Ischemia-Reperfusion Injury Through Normalization of Mitochondrial Dynamics

Deng

Chen

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Cardiac ischemia-reperfusion (I/R) injury is associated with mitochondrial dysfunction. Recent studies have reported that mitochondrial function is determined by mitochondrial dynamics. Here, we hypothesized that AMPKα2 functions as an upstream mediator that sustains mitochondrial dynamics in cardiac I/R injury and cardiomyocyte hypoxia-reoxygenation (H/R) in vitro. To test this, we analyzed cardiomyocyte viability and survival along with mitochondrial dynamics and function using western blots, qPCR, immunofluorescence, and ELISA. Our results indicated that both AMPKα2 transcription and translation were reduced by H/R injury in cardiomyocytes. Decreased AMPKα2 levels were associated with cardiomyocyte dysfunction and apoptosis. Adenovirus-mediated AMPKα2 overexpression dramatically inhibited H/Rmediated cardiomyocyte damage, possibly by increasing mitochondrial membrane potential, inhibiting cardiomyocyte oxidative stress, attenuating intracellular calcium overload, and inhibiting mitochondrial apoptosis. At the molecular level, AMPKα2 overexpression alleviated abnormal mitochondrial division and improved mitochondrial fusion through activation of the Sirt3/PGC1α pathway. This suggests AMPKα2 contributes to maintaining normal mitochondrial dynamics. Indeed, induction of mitochondrial dynamics disorder abolished the cardioprotective effects afforded by AMPKα2 overexpression. Thus, cardiac I/R-related mitochondrial dynamics disorder can be reversed by AMPKα2 overexpression in a manner dependent on the activation of Sirt3/PGC1α signaling.

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New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury

Cited by 254 publications

References 209 publications

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction

AMPKα2 Overexpression Reduces Cardiomyocyte Ischemia-Reperfusion Injury Through Normalization of Mitochondrial Dynamics

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