Sirt3 is essential for apelin‐induced angiogenesis in post‐myocardial infarction of diabetes

Hou, Xuwei; Zeng, Heng; He, Xiaochen; Chen, Jianxiong

doi:10.1111/jcmm.12453

Cited by 70 publications

(62 citation statements)

References 38 publications

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“…Experimental mice were divided into three groups: (i) C57 sham; (ii) C57 + Ad-β-gal; and (iii) C57 + Ad-SIRT3. After 2 weeks of Ad-SIRT3 or Ad-β-gal gene therapy, cardiac function was assessed using transthoracic echocardiography and the mice were then euthanized by cervical dislocation under anesthesia with isoflurane [4]. …”

Section: Methodsmentioning

confidence: 99%

“…Transthoracic echocardiograms were performed on mice using a Vevo770 High-Resolution In Vivo Micro-Imaging System equipped with a RMV 710B scanhead (VisualSonics Inc, Canada), as described previously [4;21]. The studied mouse was anesthetized by inhalation of 1.5–2% isoflurane mixed with 100% medical oxygen in an isolated chamber for induction.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial dysfunction, oxidative stress, disrupted calcium homeostasis and cellular metabolism contribute to MI injury [3]. MI activates a series of endogenous protective mechanisms including myocardial angiogenesis in the ischemic area of MI that depends on endothelial function and promotes collateral vessel formation, to maintain basic cardiac function, homeostasis and recovery [4]. It is a critical adaptive mechanism to restore blood perfusion in post-MI.…”

Section: Introductionmentioning

confidence: 99%

“…Our previous study has shown that the level of SIRT3 was decreased in the heart of db/db diabetic mice, and was associated with diabetes-induced impairment of angiogenesis, whereas over-expression of apelin increased the myocardial expression of SIRT3 and myocardial vascular density in db/db mice [18]. In addition, apelin gene therapy in streptozotocin (STZ)-induced diabetic mice improved myocardial vascular density and ameliorated MI injury in diabetic STZ-control mice, but not in STZ-SIRT3 knockout (KO) mice [4]. These studies imply an important role of SIRT3 in the process of angiogenesis and endothelial function.…”

Section: Introductionmentioning

confidence: 99%

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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Zeng

Chen

2016

International Journal of Cardiology

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Rationale Sirtuin (SIRT3), a major nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase in mitochondria, declines with aging and its ablation is associated with accelerated development of cardiovascular diseases. However, the role of SIRT3 in coronary microvascular function and post-MI recovery has not been incompletely understood. Objective The goal was to investigate whether ablation of SIRT3 causes coronary microvascular dysfunction, exacerbates post-myocardial ischemia (MI) cardiac dysfunction and impairs cardiac recovery. Methods and results Using endothelial cells (ECs) isolated from SIRT3 knockout (KO) mice, we revealed that the angiogenic capabilities were significantly reduced in SIRT3 deficient ECs. SIRT3 KO mice presented a pre-existing coronary microvascular dysfunction and microvascular rarefaction, as evidenced by a reduction in hyperemic peak diastolic blood flow velocity and coronary flow reserve (CFR), accompanied by loss of capillary-pericytes in the heart. Furthermore, SIRT3 KO mice subjected to myocardial ischemia by the ligation of left anterior descending coronary artery (LAD) exhibited more severe cardiac dysfunction together with decreased pericyte/EC coverage than that of WT mice. In contrast, overexpression of SIRT3 preserved cardiac function in post-MI mice. Immunoblot analysis further showed that the expression of angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were significantly decreased in the SIRT3-deficient ischemic hearts than those of WT ischemic hearts. This was accompanied by higher levels of cleaved caspase-3 and apoptosis. Conclusion Our results reveal a potential mechanism by which SIRT3 deletion exacerbates post-MI cardiac dysfunction and impairment of cardiac recovery involving microvascular rarefaction and pre-existing coronary microvascular dysfunction.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Zeng

Chen

2016

International Journal of Cardiology

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“…However, sirtuins are NAD + -dependent deacetylases and are unfortunately usually down-regulated in diabetes [251,[263][264][265][266][267]. If sirtuins have to be upregulated to cope with carbon stress, such approaches will certainly lead to more consumption of NAD + , the level of which is already low given the activation of poly ADP ribose polymerase and over production of NADH [36].…”

Section: Protein Acetylationmentioning

confidence: 99%

Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity

Luo¹,

Wu²,

Si-qun³

et al. 2016

Aging and disease

107

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Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD + driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD + regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.

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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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Sirt3 is essential for apelin‐induced angiogenesis in post‐myocardial infarction of diabetes

Cited by 70 publications

References 38 publications

Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity

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

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