Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction.
Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction.
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DOI：
10.1016/j.yjmcc.2017.09.007
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发表时间：
2017-11
影响因子：
5
通讯作者：
Chen JX
中科院分区：
文献类型：
--
作者：
He X;Zeng H;Chen ST;Roman RJ;Aschner JL;Didion S;Chen JX
内皮糖酵解在血管生成的调节中起着关键作用。我们研究了Sirtuin3(SIRT3)对内皮细胞(EC)糖酵解代谢、血管生成和舒张期功能的影响。我们的目的是验证这一假说，即内皮细胞中SIRT3的缺失损害了内皮糖酵解代谢和血管生成，并有助于心肌毛细血管稀疏和舒张期功能障碍的发展。利用缺乏SIRT3的内皮细胞，SIRT3被发现调节线粒体呼吸和糖酵解之间的代谢转换。SIRT3基因敲除(KO)-ECs表现出更高的线粒体呼吸和活性氧物种(ROS)的形成。SIRT3基因敲除(KO)-ECs表现出糖酵解酶PFKFB3的表达减少，糖酵解和血管生成减少。阻断PFKFB3可减少内皮细胞糖酵解，下调血管内皮生长因子和血管生成素-1的表达。内皮细胞中sirt3的缺失也削弱了缺氧诱导的缺氧诱导的α、血管内皮生长因子和血管紧张素转换酶1的表达，并减少了血管生成。在体内，内皮特异性SIRT3 KO(ECKO)小鼠表现出心肌毛细血管稀疏，冠状动脉血流储备(CFR)减少和舒张期功能障碍。组织学研究进一步表明，内皮细胞中SIRT3基因敲除显著增加了冠状动脉血管周围纤维化。这些结果提示SIRT3在调节血管内皮细胞功能和心功能方面发挥作用。SIRT3消融导致EC糖酵解代谢和血管生成信号转导受损，这可能是SIRT3 EKO小鼠冠脉微血管稀疏和舒张期功能障碍的原因之一。
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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DOI：
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发表时间：
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影响因子：
4.8
作者：
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