Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis.
Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis.
复制标题
Sirtuin 3 缺陷通过损害血管生成加速高血压心脏重塑
DOI：
10.1161/jaha.117.006114
复制
发表时间：
2017-08-19
影响因子：
5.4
通讯作者：
Shen W
中科院分区：
文献类型：
--
作者：
Wei T;Huang G;Gao J;Huang C;Sun M;Wu J;Bu J;Shen W
新出现的证据表明，血管生成受损可能有助于高血压诱导的心脏重塑。烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶Sirtuin 3（SIRT 3）具有调节血管生成的潜力，但尚未得到证实。因此，本研究的目的是检查SIRT 3介导的血管生成和心脏重塑之间的关系。我们的实验是在SIRT 3敲除和年龄匹配的野生型小鼠中进行的，这些小鼠输注了血管紧张素II（1400 ng/kg/min）或盐水14天。血管紧张素II输注后，SIRT 3敲除小鼠与野生型小鼠相比，心脏组织中出现了更严重的微血管稀疏和功能性缺氧。这些事件伴随线粒体功能障碍和I型胶原和III型胶原表达增强，导致心脏纤维化。沉默SIRT 3促进血管紧张素II诱导的异常Pink/Parkin乙酰化和受损的线粒体自噬，而过多的线粒体活性氧产生限制了原代小鼠心脏微血管内皮细胞的血管生成能力。此外，心脏微血管内皮细胞中的SIRT 3过表达增强了Pink/Parkin介导的线粒体自噬，减弱了线粒体活性氧的产生，并恢复了血管出芽和管形成。与此同时，与具有类似刺激的野生型小鼠相比，内皮细胞特异性SIRT 3转基因小鼠显示出减少的纤维化，以及改善的心脏功能和微血管网络。总的来说，这些发现表明SIRT 3可以通过减弱由线粒体自噬缺陷引起的线粒体功能障碍来促进血管生成。
Emerging evidence indicates that impaired angiogenesis may contribute to hypertension‐induced cardiac remodeling. The nicotinamide adenine dinucleotide–dependent deacetylase Sirtuin 3 (SIRT3) has the potential to modulate angiogenesis, but this has not been confirmed. As such, the aim of this study was to examine the relationship between SIRT3‐mediated angiogenesis and cardiac remodeling. Our experiments were performed on SIRT3 knockout and age‐matched wild‐type mice infused with angiotensin II (1400 ng/kg per minute) or saline for 14 days. After angiotensin II infusion, SIRT3 knockout mice developed more severe microvascular rarefaction and functional hypoxia in cardiac tissues compared with wild‐type mice. These events were concomitant with mitochondrial dysfunction and enhanced collagen I and collagen III expression, leading to cardiac fibrosis. Silencing SIRT3 facilitated angiotensin II–induced aberrant Pink/Parkin acetylation and impaired mitophagy, while excessive mitochondrial reactive oxygen species generation limited angiogenic capacity in primary mouse cardiac microvascular endothelial cells. Moreover, SIRT3 overexpression in cardiac microvascular endothelial cells enhanced Pink/Parkin‐mediated mitophagy, attenuated mitochondrial reactive oxygen species generation, and restored vessel sprouting and tube formation. In parallel, endothelial cell–specific SIRT3 transgenic mice showed decreased fibrosis, as well as improved cardiac function and microvascular network, compared with wild‐type mice with similar stimuli. Collectively, these findings suggest that SIRT3 could promote angiogenesis through attenuating mitochondrial dysfunction caused by defective mitophagy.