Metabolic Flexibility and Dysfunction in Cardiovascular Cells

Vallerie, Sara N.; Bornfeldt, Karin E.

doi:10.1161/atvbaha.115.306226

Cited by 31 publications

(19 citation statements)

References 60 publications

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“…Despite immediate access to oxygen in the blood stream, healthy ECs rely on glycolysis rather than oxidative phosphorylation to maintain proper function in response to hypoxia and nutrient deprivation [15, 37]. ECs can increase glycolytic flux in part, by upregulating the expression of PFKFB3 [15, 38].…”

Section: Discussionmentioning

confidence: 99%

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Zeng

Chen

et al. 2017

Journal of Molecular and Cellular Cardiology

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Endothelial glycolysis plays a critical role in the regulation of angiogenesis. We investigated the role of Sirtuin 3 (SIRT3) on endothelial cell (EC) glycolytic metabolism, angiogenesis, and diastolic function. Our aim was to test the hypothesis that loss of SIRT3 in ECs impairs endothelial glycolytic metabolism and angiogenesis and contributes to myocardial capillary rarefaction and the development of diastolic dysfunction. Using SIRT3 deficient ECs, SIRT3 was found to regulate a metabolic switch between mitochondrial respiration and glycolysis. SIRT3 knockout (KO)-ECs exhibited higher mitochondrial respiration and reactive oxygen species (ROS) formation. SIRT3 knockout (KO)-ECs exhibited a reduction in the expression of glycolytic enzyme, PFKFB3, and a fall in glycolysis and angiogenesis. Blockade of PFKFB3 reduced glycolysis and downregulated expression of VEGF and Angiopoietin-1 (Ang-1) in ECs. Deletion of SIRT3 in ECs also impaired hypoxia-induced expression of HIF-2α, VEGF, and Ang-1, as well as reduced angiogenesis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited a myocardial capillary rarefaction together with a reduced coronary flow reserve (CFR) and diastolic dysfunction. Histologic study further demonstrated that knockout of SIRT3 in ECs significantly increased perivascular fibrosis in the coronary artery. These results implicate a role of SIRT3 in modulating endothelial function and cardiac function. Ablation of SIRT3 leads to impairment of EC glycolytic metabolism and angiogenic signaling, which may contribute to coronary microvascular rarefaction and diastolic dysfunction in SIRT3 ECKO mice.

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Section: Discussionmentioning

confidence: 99%

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Zeng

Chen

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…Vice versa, increased glycolysis induced by overexpression of GLUT1 leads to enhanced proinflammatory cytokine secretion [70]. However, in an experimental model in vivo, the increased glucose uptake did not stimulate inflammatory activation of peritoneal cells upon ex vivo stimulation with LPS, neither did it affect the development of atherosclerosis in Ldlr −/− mice in vivo [71], suggesting that increased glucose supply alone is not sufficient to drive inflammatory activation and atherosclerosis in non-activated myeloid cells [72]. Possibly, synergism of glycolysis with other metabolic or immunologic pathways is necessary to induce the inflammatory phenotype in monocytes.…”

Section: Can Trained Immunity Contribute To Atherosclerosis In Diabetmentioning

confidence: 99%

Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?

Diepen

Thiem

Stienstra

et al. 2016

Cell. Mol. Life Sci.

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Diabetes strongly predisposes to cardiovascular disease (CVD), the leading cause of mortality in these patients, as well as in the entire population. Hyperglycemia is an important cardiovascular risk factor as shown by the observation that even transient periods of hyperglycemia, despite return to normoglycemia during follow-up, increase the risk for CVD, a phenomenon termed ‘hyperglycemic memory’. The molecular mechanisms underlying this phenomenon remain largely unknown. As inflammation plays an important role in the pathogenesis of atherosclerosis, we propose that long-term functional reprogramming of monocytes and macrophages, induced by hyperglycemia, plays an important role in the phenomenon of hyperglycemic memory leading to cardiovascular complications in patients with diabetes. In this review, we discuss recent insights showing that innate immune cells possess the capacity to reprogram their function through epigenetically mediated rewiring of gene transcription, a process termed ‘trained immunity’. The long-term reprogramming of monocytes can be induced by microbial as well as metabolic products, and involves a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. We hypothesize that hyperglycemia in diabetes patients induces long-term activation of monocytes and macrophages through similar mechanisms, thereby contributing to plaque development and subsequent macrovascular complications.

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“…Studies have found an association between impaired metabolic flexibility (also known as metabolic inflexibility) and type 2 diabetes mellitus, cardiovascular diseases and metabolic syndrome [12][13][14][15] . Other studies have narrowed down the effects of metabolic inflexibility in the adipose tissue on the impairment of adipokine signalling as well as the clearance of circulating non-esterified fatty acids (as reviewed in 11,16 ).…”

mentioning

confidence: 99%

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

Tareen

Kutmon

Kok

et al. 2020

Sci Rep

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Obesity is a global epidemic, contributing significantly to chronic non-communicable diseases, such as type 2 diabetes mellitus, cardiovascular diseases and metabolic syndrome. Metabolic flexibility, the ability of organisms to switch between metabolic substrates, is found to be impaired in obesity, possibly contributing to the development of chronic illnesses. Several studies have shown the improvement of metabolic flexibility after weight loss. In this study, we have mapped the cellular metabolism of the adipose tissue from a weight loss study to stratify the cellular metabolic processes and metabolic flexibility during weight loss. We have found that for a majority of the individuals, cellular metabolism was downregulated during weight loss, with gene expression of all major cellular metabolic processes (such as glycolysis, fatty acid β-oxidation etc.) being lowered during weight loss and weight maintenance. Parallel to this, the gene expression of immune system related processes involving interferons and interleukins increased. previously, studies have indicated both negative and positive effects of post-weight loss inflammation in the adipose tissue with regards to weight loss or obesity and its co-morbidities; however, mechanistic links need to be constructed in order to determine the effects further. Our study contributes towards this goal by mapping the changes in gene expression across the weight loss study and indicates possible cross-talk between cellular metabolism and inflammation.

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Metabolic Flexibility and Dysfunction in Cardiovascular Cells

Cited by 31 publications

References 60 publications

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive?

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

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