Decreased ATP production and myocardial contractile reserve in metabolic heart disease

Luptak, Ivan; Sverdlov, Aaron L.; Panagia, Marcello; Qin, Fuzhong; Pimentel, David R.; Croteau, Dominique; Siwik, Deborah A.; Ingwall, Joanne S.; Bachschmid, Markus; Balschi, James A.

doi:10.1016/j.yjmcc.2018.01.017

Cited by 79 publications

(67 citation statements)

References 56 publications

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“…To evoke a more drastic deterioration of cardiac function by the HFD, it is possible that a longer exposure of the mice to the HFD is required. Indeed, metabolic heart disease was shown to be induced in C57BL/6J mice by exposure to a HFD and high‐sucrose diet for 4 or 8 months (Sverdlov et al, ; Sverdlov et al, ; Luptak et al, ). A limitation of our study is therefore that the animals were only exposed to the diets for 15 weeks.…”

Section: Discussionmentioning

confidence: 99%

ADAMTS5 deficiency in mice does not affect cardiac function

Hemmeryckx

Carai

Lijnen

2019

Cell Biology International

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The aggrecanase ADAMTS5 (A Disintegrin and Metalloproteinase with ThromboSpondin type 1 motifs, member 5) and the cleavage of its substrate versican have been implicated in the development of heart valves. Furthermore, ADAMTS5 deficiency was shown to protect against diet‐induced obesity, a known risk factor for cardiovascular disease. Therefore, in this study, we investigated the potential role of ADAMTS5 in cardiac function using ADAMTS5‐deficient (Adamts5−/−) mice and their wild‐type (Adamts5+/+) counterparts exposed to a standard‐fat or a high‐fat diet (HFD). Eight‐weeks‐old Adamts5−/− and Adamts5+/+ mice were exposed to each diet for 15 weeks. Cardiac function and electrophysiology were analyzed by transthoracic echocardiogram and electrocardiogram at the end of the study. Cleavage of versican, as detected by the appearance of the DPEEAE neo‐epitope on western blotting with protein extracts, was defective in the heart of HFD‐treated Adamts5−/− as compared with Adamts5+/+ mice. ADAMTS5 deficiency led to statistically significant increases in diastolic posterior wall thickness (0.94 ± 0.023 vs. 0.82 ± 0.036 mm; P = 0.0056) and left ventricle volume (47 ± 4.5 vs. 31 ± 2.5 μL; P = 0.0043) in comparison to Adamts5+/+ mice, but only in animals on a HFD. Cardiac function parameters such as ejection fraction, fractional shortening, and stroke volume were unaffected by ADAMTS5 deficiency or diet. Electrocardiogram analysis revealed no ADAMTS5‐specific changes in either diet group. Thus, in the absence of ADAMTS5, cleavage of versican in the cardiac extracellular matrix is impaired, but cardiac function, even upon exposure to a HFD, is not markedly affected.

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Section: Discussionmentioning

confidence: 99%

ADAMTS5 deficiency in mice does not affect cardiac function

Hemmeryckx

Carai

Lijnen

2019

Cell Biology International

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“…Expression of genes involved in metabolism was reordered toward WT levels in OGT TG x OGA TG hearts. The role of depressed energetics and deranged metabolism is a consistent finding in dilated cardiomyopathy in patients 10,25,27 furthermore, excessive O-GlcNAcylation is associated with defects in oxidative phosphorylation, in part, by actions in mitochondria 11,23,31,35,36 . We found reduced expression of a number of genes encoding complex I proteins, loss of complex I proteins, and decreased complex I activity in OGT TG hearts.…”

Section: Discussionmentioning

confidence: 83%

“…a. Representative western blot and b. summary data for total O-GlcNAc modified protein levels from whole heart lysates of [8][9][10][11][12] week old mice. Hearts were removed 14 days after transaortic banding (TAB) or sham surgery (n = 5 mice/group).…”

Section: Figmentioning

confidence: 99%

ExcessiveO- GlcNAcylation causes heart failure and sudden death

Umapathi

Banerjee

Zachara

et al. 2020

Preprint

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Background:Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation, a post-translational modification of intracellular proteins, serves as a potent transducer of cellular stress. Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Methods:We developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAclyation independent of pathological stress. Results:We found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had O-GlcNAcylation and cardiac function similar to wild type littermate controls. However, OGA trangenic hearts were resistant to pathological stress induced by pressure overload and had attenuated myocardial O-GlcNAcylation levels, decreased pathological hypertrophy and improved systolic function. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death despite persistant elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of 3 complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology. Conclusions:Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is an effective therapy against pressure overload induced heart failure. Attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy. Clinical Perspective What is new? Cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation.Here we provide new genetic mouse models to control myocardial O-GlcNAcylation independent of pathological stress.  Genetically increased myocardial O-GlcNAcylation causes progressive dilated cardiomyopathy and premature death, while genetic reduction of myocardial O-GlcNAcylation is protective against pathological hypertrophy caused by transaortic banding.  Excessive myocardial O-GlcNAcylation decreases activity and expression of mitochondrial complex I. What are the clinical implications?  Increased myocardial O-GlcNAcylation has been shown to be associated with a diverse range of clinical heart failure including aortic stenosis, hypertension, ischemia and diabetes.  Using novel genetic mouse models we have provided new proof of concept data that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy.  We have ...

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“…For example, Luptak et al could show that mitochondrial ATP production is markedly reduced in metabolic heart disease. 8 In human HFpEF, a decreased creatine phosphate/ATP ratio was observed signifying energy deficiency as well. 9 Several drugs and substances targeting mitochondrial bioenergetics are currently evaluated in clinical trials for patients with HFpEF.…”

Section: Mitochondrial Calcium In Heart Failure With Preserved Ejectimentioning

confidence: 99%

“…The intricacies of mitochondrial remodelling become apparent when data from other groups in models mimicking conditions associated with the development of HFpEF are considered. For example, Luptak et al could show that mitochondrial ATP production is markedly reduced in metabolic heart disease . In human HFpEF, a decreased creatine phosphate/ATP ratio was observed signifying energy deficiency as well …”

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confidence: 99%