NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

Xu, Weiyi; Li, Le; Zhang, Lilei

doi:10.3389/fphys.2020.00901

Cited by 24 publications

(19 citation statements)

References 262 publications

(355 reference statements)

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“…However, under HFD feeding, Grx3 CKO DIO mice showed a significant increase in the NAD + /NADH ratio (Figure S1), indicating a redox imbalance in the hearts. There is growing evidence that cardiac energy metabolism and redox balance are crucial for the development and progression of heart diseases including heart failure [17][18][19]. Thus, these results suggest that deletion of Grx3 in the Grx3 CKO DIO hearts leads to oxidative stress and redox imbalance that are detrimental to cardiac function and eventually cause the progression of heart failure in these mice (see below).…”

Section: Enhanced Ros Production In the Heart Of Grx3 Cko Mice Independently Of Feeding Regimementioning

confidence: 95%

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

Cheng¹,

Mo²,

Donelson³

et al. 2021

Int. J. Biol. Sci.

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Obesity is often associated with metabolic dysregulation and oxidative stress with the latter serving as a possible unifying link between obesity and cardiovascular complications. Glutaredoxins (Grxs) comprise one of the major antioxidant systems in the heart. Although Grx3 has been shown to act as an endogenous negative regulator of cardiac hypertrophy and heart failure, its metabolic impact on cardiac function in diet-induced obese (DIO) mice remains largely unknown. In the present study, analysis of Grx3 expression indicated that Grx3 protein levels, but not mRNA levels, were significantly increased in the hearts of DIO mice. Cardiac-specific Grx3 deletion (Grx3 CKO) mice were viable and grew indistinguishably from their littermates after being fed a high fat diet (HFD) for one month, starting at 2 months of age. After being fed with a HFD for 8 months (starting at 2 months of age); however, Grx3 CKO DIO mice displayed left ventricular systolic dysfunction with a significant decrease in ejection fraction and fractional shortening that was associated with heart failure. ROS production was significantly increased in Grx3 CKO DIO cardiomyocytes compared to control cells. Gene expression analysis revealed a significant decline in the level of transcripts corresponding to genes associated with processes such as fatty acid uptake, mitochondrial fatty acid transport and oxidation, and citrate cycle in Grx3 CKO DIO mice compared to DIO controls. In contrast, an increase in the level of transcripts corresponding to genes associated with glucose uptake and utilization were found in Grx3 CKO DIO mice compared to DIO controls. Taken together, these findings indicate that Grx3 may play a critical role in redox balance and as a metabolic switch in cardiomyocytes contributing to the development and progression of heart failure.

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Section: Enhanced Ros Production In the Heart Of Grx3 Cko Mice Independently Of Feeding Regimementioning

confidence: 95%

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

Cheng¹,

Mo²,

Donelson³

et al. 2021

Int. J. Biol. Sci.

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show abstract

“…Therefore, NAD + plays a central role in oxidative phosphorylation, making it an attractive target for interventions in cardiac diseases including AF. Indeed, accumulating studies have already shown that boosting NAD + levels improve mitochondrial function in cardiovascular diseases, such as heart failure and ischemic conditions [118][119][120], which has been reviewed in-depth [121]. Collectively, these findings suggest that NAD + homeostasis improves mitochondrial function by attenuation of oxidative stress and DNA damage [118].…”

Section: Nutraceuticals To Conserve Mitochondrial Functionmentioning

confidence: 95%

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery

Pool

Wijdeveld

Groot

et al. 2021

IJMS

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Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.

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“…3,4 The decline in NAD + is associated with the development of various CVDs like cardiac hypertrophy and heart failure, while supplementation of NAD + improves cardiac function. 5 Interestingly, the beneficial effects of NAD + supplementation in the heart is mediated by a family of NAD + -dependent enzymes called sirtuins. 6 Sirtuins, the mammalian homologs of the yeast Sir2, are post-translational modification enzymes with diverse histone and nonhistone targets.…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of Sirtuin 2 in cardiovascular diseases

et al. 2021

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Sirtuins are a family of NAD+‐dependent deacetylases implicated in a wide variety of age‐associated pathologies, including cardiovascular disorders. Among the seven mammalian sirtuins, SIRT2 modulates various cellular processes through the deacetylation or deacylation of their target proteins. Notably, the levels of SIRT2 in the heart decline with age and other pathological conditions, leading to cardiovascular dysfunction. In the present review, we discuss the emerging roles of SIRT2 in cardiovascular dysfunction and heart failure associated with factors like age, hypertension, oxidative stress, and diabetes. We also discuss the potential of using inhibitors to study the unexplored role of SIRT2 in the heart. While SIRT2 undoubtedly plays a crucial role in the cardiovascular system, its functions are only beginning to be understood, making it an attractive candidate for further research in the field.

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NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

Cited by 24 publications

References 262 publications

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

Crucial Role of Mammalian Glutaredoxin 3 in Cardiac Energy Metabolism in Diet-induced Obese Mice Revealed by Transcriptome Analysis

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery

Emerging roles of Sirtuin 2 in cardiovascular diseases

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