NAD+ administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux

Zhang, Youjun; Zhang, Mingchao; Zhao, Xiaona; Shi, Kailei; Ye, Maoqing; Tian, Jianqiu; Guan, Sheng; Ying, Weihai; Qu, Xinkai

doi:10.1007/s00395-020-0817-z

Cited by 41 publications

(38 citation statements)

References 41 publications

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“…The microvascular ultrastructure in the heart was evaluated using electron photomicrographs (EM). Heart samples were fixed in 5% glutaraldehyde and 4% paraformaldehyde in 0.1 M sodium cacodylate buffer (pH 7.4) with 0.05% CaCl 2 for 24 h. After washing in 0.1 M sodium cacodylate buffer, tissues were postfixed in 1% OsO4 and 0.1 M cacodylate buffer overnight, dehydrated and embedded in Embed 812 resin ( Zhang et al, 2020 ). The sections were stained with 2% uranyl acetate followed by 0.4% lead citrate and viewed with a Philips 400 electron microscope (Electron Microscopy Sciences).…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

Tian

Zhang

2021

Front. Cell Dev. Biol.

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Our previous research has shown that type-2a Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) undergoes posttranscriptional oxidative modifications in cardiac microvascular endothelial cells (CMECs) in the context of excessive cardiac oxidative injury. However, whether SERCA2a inactivity induces cytosolic Ca2+ imbalance in mitochondrial homeostasis is far from clear. Mitofusin2 (Mfn2) is well known as an important protein involved in endoplasmic reticulum (ER)/mitochondrial Ca2+ tethering and the regulation of mitochondrial quality. Therefore, the aim of our study was to elucidate the specific mechanism of SERCA2a-mediated Ca2+ overload in the mitochondria via Mfn2 tethering and the survival rate of the heart under conditions of cardiac microvascular ischemic injury. In vitro, CMECs extracted from mice were subjected to 6 h of hypoxic injury to mimic ischemic heart injury. C57-WT and Mfn2KO mice were subjected to a 1 h ischemia procedure via ligation of the left anterior descending branch to establish an in vivo cardiac ischemic injury model. TTC staining, immunohistochemistry and echocardiography were used to assess the myocardial infarct size, microvascular damage, and heart function. In vitro, ischemic injury induced irreversible oxidative modification of SERCA2a, including sulfonylation at cysteine 674 and nitration at tyrosine 294/295, and inactivation of SERCA2a, which initiated calcium overload. In addition, ischemic injury-triggered [Ca2+]c overload and subsequent [Ca2+]m overload led to mPTP opening and ΔΨm dissipation compared with the control. Furthermore, ablation of Mfn2 alleviated SERCA2a-induced mitochondrial calcium overload and subsequent mito-apoptosis in the context of CMEC hypoxic injury. In vivo, compared with that in wild-type mice, the myocardial infarct size in Mfn2KO mice was significantly decreased. In addition, the findings revealed that Mfn2KO mice had better heart contractile function, decreased myocardial infarction indicators, and improved mitochondrial morphology. Taken together, the results of our study suggested that SERCA2a-dependent [Ca2+]c overload led to mitochondrial dysfunction and activation of Mfn2-mediated [Ca2+]m overload. Overexpression of SERCA2a or ablation of Mfn2 expression mitigated mitochondrial morphological and functional damage by modifying the SERCA2a/Ca2+-Mfn2 pathway. Overall, these pathways are promising therapeutic targets for acute cardiac microvascular ischemic injury.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

Tian

Zhang

2021

Front. Cell Dev. Biol.

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“…Echocardiographic measurements were performed on three consecutive cardiac cycles using the leading edge-to-leading edge method. Left ventricular ejection fraction (LVEF), left ventricular diastolic dimension (LVDd), and FS were measured or calculated with software [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

et al. 2021

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Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPR mt ) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPR mt , their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPR mt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1 CKO ) mice. Notably, supplementation with a mitophagy inducer had no impact on UPR mt , whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPR mt in LPS-treated hearts. In contrast, enhancement of endogenous UPR mt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1 CKO mice. Lastly, once UPR mt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPR mt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPR mt , a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPR mt activation had no negative impact on mitophagy, UPR mt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPR mt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPR mt targeting in the treatment of myocardial stress.

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“…We found NAD + of different concentrations had no significant effect on cell viability (Fig. 6A), and we chose NAD + concentration of 5 mM for NAD + experiment in hypoxia-challenged microglia [39] . Sirt1 overexpression was confirmed by Western blot analysis (Fig.…”

Section: Nad + and Overexpression Of Sirt1 Reduced The Generation Of mentioning

confidence: 99%

NAD+ Improves Cognitive Function and Reduces Neuroinflammation By Ameliorating Mitochondrial Damage and Decreasing ROS Production in Chronic Cerebral Hypoperfusion Models Through Sirt1/PGC-1α Pathway

Zhao

Zhang

Zheng

et al. 2021

Preprint

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Background: Microglial mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. NAD + shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. Methods: The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD + for 8 weeks. Behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD + treatment effects on mitochondrial injury and neuroinflammation. Results: NAD + administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1 , while NAD + treatment markedly reversed their decrease. In vitro study confirmed that NAD + administration had protective effects on hypoxia induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD + treatment in BV2 microglia.Conclusions: NAD + ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway. Keywords: Chronic cerebral hypoperfusion, microglia, NAD + , mitochondria, ROS

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NAD+ administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux

Cited by 41 publications

References 41 publications

RETRACTED: Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

RETRACTED: Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

NAD+ Improves Cognitive Function and Reduces Neuroinflammation By Ameliorating Mitochondrial Damage and Decreasing ROS Production in Chronic Cerebral Hypoperfusion Models Through Sirt1/PGC-1α Pathway

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