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

He, Xiaochen; Zeng, Heng; Chen, Sean T.; Roman, Richard J.; Aschner, Judy L.; Didion, Sean P.; Chen, Jian Xiong

doi:10.1016/j.yjmcc.2017.09.007

Cited by 88 publications

(110 citation statements)

References 44 publications

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“…Consistent with these clinical observation, our study revealed that global SIRT3 KO mice develop coronary microvascular dysfunction and diastolic dysfunction, associated with decreased myocardial capillary density and pericyte coverage (He et al, ). Similarly, endothelial‐specific SIRT3 knockout (ECKO) mice also exhibit decreased coronary function and diastolic function (He et al, ). These studies indicate that endothelial function plays an important role in cardiac homeostasis involving SIRT3‐mediated cellular function.…”

Section: Sirt3 In Cardiac Function and Cardiovascular Diseasementioning

confidence: 99%

Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

Zeng

Chen

2018

Journal Cellular Physiology

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Sirtuin 3 (SIRT3) a mitochondrial enzyme that plays an important role in energy homeostasis, cardiac remodeling, and heart failure (HF). The expression of SIRT3 declines with advanced age, cardiovascular, and metabolic diseases. Accumulating evidence suggests that SIRT3 plays a critical role in protecting the heart from cardiac hypertrophy, cardiac dysfunction associated with HF, and in the protection of cardiac cells from stress-mediated cell death. Clinical studies have demonstrated that HF with preserved ejection fraction (HFpEF) in patients present with abnormalities in coronary microcirculation related to endothelial dysfunction and coronary microvascular rarefaction. Although SIRT3-mediated regulation of mitochondrial homeostasis and heart function has been intensively investigated, the effect of SIRT3 on endothelial cell (EC) glycolytic metabolism and microvascular function has not been well studied. ECs utilize glycolysis for generating ATP rather than oxidative phosphorylation to maintain their normal functions and promote angiogenesis and EC-cardiomyocyte interactions. Emerging evidence indicates that SIRT3 is involved in the regulation of endothelial metabolism and angiogenesis and thus affects the development of cardiovascular diseases associated with aging. This review will discuss the current knowledge of SIRT3 and its functional role on endothelial metabolism, cardiac function, and cardiovascular diseases.

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Section: Sirt3 In Cardiac Function and Cardiovascular Diseasementioning

confidence: 99%

Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

Zeng

Chen

2018

Journal Cellular Physiology

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“…Therefore, increased Ang-2 and TGF-β in the liver tissues may be responsible for hepatic fibrosis in the PHD2 EC KO mice. In addition, inhibition of PFKFB3 has been shown to increase Ang-2 expression in the EC [37]. Treatment with ANP has been shown to reduce liver fibrosis [38].…”

Section: Discussionmentioning

confidence: 99%

Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Zhou

Zeng

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver disease is a leading cause of high mortality and morbidity worldwide. The aim of the present study is to investigate the regulatory role of prolyl hydroxylase-2 (PHD2)-hypoxia-inducible factor-2a (HIF-2α) axis on nonalcoholic fatty liver disease (NAFLD) and to explore the potential mechanisms by which endothelial (EC)-specific PHD2 deficiency regulates hepatic steatosis and fibrosis. Methods: In the endothelial-specific PHD2 knockout (PHD2^ECKO) mouse fed with normal diet or high fat diet (HFD), liver lipid accumulation and fibrosis were measured by Oil Red O and Masson trichrome staining. The fat and body weight (FW/BW) ratio and glucose tolerance were measured. The expression of HIF-2α, atrial natriuretic peptide (ANP), angiopoietin-2 (Ang-2), and transforming growth factor-b (TGF-β) were analyzed by western blot analysis. Results: The steatosis and fibrosis were significantly increased in the PHD2^ECKO mice. FW/BW ratio was significantly increased in the PHD2^ECKO mice. Moreover, knockout of endothelial PHD2 resulted in an impairment of glucose tolerance in mice. Western blot analysis showed that the expression of HIF-2α in liver tissues was not significantly increased. Interestingly, the expression of ANP was decreased, and Ang-2 and TGF-β levels were significantly increased in the liver of PHD2^ECKO mice. The FW/BW ratio was also significantly increased in the PHD2^ECKO mice fed with HFD for 16 weeks. Feeding HFD resulted in a significant increase in hepatic steatosis in the control PHD2^f/f mice, but did not further enhance hepatic steatosis in the PHD2^ECKO mice. Conclusions: We concluded that the endothelial PHD2 plays a critical role in hepatic steatosis and fibrosis, which may be involved in the regulation of ANP and Ang-2/TGF-β signaling pathway, but not the HIF-2α expression.

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“…Cellular bioenergetics was measured using a Seahorse XFe24 extracellular flux analyzer in intact cardiomyocytes. We conducted glycolysis stress testing following the manufacturer's instructions as previously reported [ 25 ]. Glycolysis stress test: cells were incubated in glucose-free Seahorse assay media supplemented with 1 mM pyruvate at 37°C in an incubator without CO 2 for 1 h prior to the assay.…”

Section: Methodsmentioning

confidence: 99%

Cardioprotective Natural Compound Pinocembrin Attenuates Acute Ischemic Myocardial Injury via Enhancing Glycolysis

Zheng

Wan

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Purpose. Emerging evidence has shown that pinocembrin protects the myocardium from ischemic injury in animals. However, it is unknown whether it has cardioprotection when given at the onset of reperfusion. Also, mechanisms mediating the cardioprotective actions of pinocembrin were largely unknown. Thus, this study is aimed at investigating the effects of pinocembrin postconditioning on ischemia-reperfusion (I/R) injury and the underlying mechanisms. Methods. The in vivo mouse model of myocardial I/R injury, ex vivo isolated rat heart with global I/R, and in vitro hypoxia/reoxygenation (H/R) injury model for primary cardiomyocytes were used. Results. We found that pinocembrin postconditioning significantly reduced the infarct size and improved cardiac contractile function after acute myocardial I/R. Mechanically, in primary cardiomyocytes, we found that pinocembrin may confer protection in part via direct stimulation of cardiac glycolysis via promoting the expression of the glycolytic enzyme, PFKFB3. Besides, PFKFB3 inhibition abolished pinocembrin-induced glycolysis and protection in cardiomyocytes. More importantly, PFKFB3 knockdown via cardiotropic adeno-associated virus (AAV) abrogated cardioprotective effects of pinocembrin. Moreover, we demonstrated that HIF1α is a key transcription factor driving pinocembrin-induced PFKFB3 expression in cardiomyocytes. Conclusions. In conclusion, these results established that the acute cardioprotective benefits of pinocembrin are mediated in part via enhancing PFKFB3-mediated glycolysis via HIF1α, which may provide a new therapeutic target to impede the progression of myocardial I/R injury.

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

Cited by 88 publications

References 44 publications

Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Cardioprotective Natural Compound Pinocembrin Attenuates Acute Ischemic Myocardial Injury via Enhancing Glycolysis

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