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

He, Xiaochen; Zeng, Heng; Chen, Jianxiong

doi:10.1016/j.ijcard.2016.04.092

Cited by 73 publications

(74 citation statements)

References 44 publications

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“…Meanwhile, He et al . found that SIRT3 knock out impaired post-myocardial ischemia cardiac function by causing coronary microvascular dysfunction40. Notably, several studies also demonstrated the key role of SIRT3 in reducing myocardial injury in diabetic state.…”

Section: Discussionmentioning

confidence: 96%

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

Gong

Duan

et al. 2017

Sci Rep

168

137

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Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, H2O2 generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process.

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Section: Discussionmentioning

confidence: 96%

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

Gong

Duan

et al. 2017

Sci Rep

168

137

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“…The coronary flow reserve (CFR) is calculated as the ratio of hyperemic peak diastolic flow velocity to baseline peak diastolic flow velocity [19, 21]. …”

Section: Methodsmentioning

confidence: 99%

“…The 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a key regulator of glycolysis in endothelial cells (EC), that has been shown to promote angiogenic sprouting [15, 17, 18]. Our recent study demonstrated a significant reduction of PFKFB3 expression and impaired angiogenesis in the heart of SIRT3 KO mice [19]. However, a direct role of SIRT3 in endothelial glycolytic metabolism, angiogenesis and diastolic function is unknown and has not been studied previously.…”

Section: Introductionmentioning

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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“…Left thoracotomy was performed to expose the heart. LAD was ligated using an 8-0 nylon suture [18,19]. Twenty four hours or 2 weeks after surgery, mice were sacrificed and heart tissue was collected.…”

Section: Methodsmentioning

confidence: 99%

“…Anesthesia was kept with 1–1.5% isoflurane, maintaining the heart rate between 400 and 450 beats per minute. M-mode cine loops 1were recorded and analyzed by High-Frequency Ultrasound Imaging software (VisualSonics Inc., Canada) to assess myocardial parameters and cardiac functions of left ventricle, including left ventricle end-systolic diameter (LVESD), left ventricle end-diastolic diameter (LVEDD), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), thickness of the left ventricle anterior wall (LVAW) and posterior wall (LVPW) at end systole and end diastole, and stroke volume (SV), cardiac output (CO), as well as ejection fraction (EF%) and fractional shortening (FS%) [18,19]. …”

Section: Methodsmentioning

confidence: 99%

Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia

Tao

Zeng

Zhang

et al. 2017

International Journal of Cardiology

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Rationale Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development. Objective This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI. Approach and results Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2+/Sca1+ and NG2+/c-kit+ progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2 weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b+ macrophage infiltration into ischemic areas compared to that of WT mice. Conclusion Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the preexisting coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation.

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

Cited by 73 publications

References 44 publications

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

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

Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia

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