Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction
Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction
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DOI：
10.1152/ajpheart.00281.2014
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发表时间：
2014-12-15
影响因子：
4.8
通讯作者：
Goligorsky, Michael S.
中科院分区：
文献类型：
--
作者：
Maizel, Julien;Xavier, Sandhya;Goligorsky, Michael S.
不协调的心肌生长和血管生成可以解释左心室（LV）肥大随着年龄的增长而进展为心力衰竭。Sirtuin 1的表达随着年龄的增长而下降，因此我们探讨了血管生成和Sirtuin 1在心肌病发展中所起的作用。我们比较了10- 15周龄（wo）、30-40 wo和61-70 wo内皮Sirtuin 1缺失（Sirt 1（endo-/-））小鼠及其相应敲除对照（Sirt 1（Flox）/（Flox））的心脏功能。30-40周后，Sirt 1（endo-/）-动物表现出舒张功能障碍（DD），LV中Serca 2a mRNA表达降低，与对照动物相比毛细血管密度降低，尽管VEGFa mRNA表达相似。然而，左室纤维化和缺氧诱导因子（HIF）1 α表达没有差异。与对照TAC动物相比，在Sirt 1（endo-/）中创建横向主动脉缩窄（TAC）引起更严重的DD和LV纤维化。尽管Sirt 1（endo-/）-TAC动物的VEGFa mRNA表达没有差异，HIF 1 α的蛋白表达更高，但毛细血管密度仍然降低。在培养的内皮细胞中，Sirtuin 1抑制剂可降低VEGF受体FLT 1和FLK 1的mRNA表达。Sirt 1（endo-/-）小鼠主动脉外植体的离体毛细血管发芽显示对VEGF的血管生成反应受损。总之，数据证明1）血管生成缺陷先于DD的发展; 2）内皮Sirtuin 1在非应激条件下和在正常老化期间的可分配性;和3）在用LV过载攻击的Sirt 1（endo-/-）小鼠中受损的血管生成适应和加重的DD。
Discordant myocardial growth and angiogenesis can explain left ventricular (LV) hypertrophy progressing toward heart failure with aging. Sirtuin 1 expression declines with age; therefore we explored the role played by angiogenesis and Sirtuin 1 in the development of cardiomyopathy. We compared the cardiac function of 10-to 15-wk-old (wo), 30-40 wo, and 61-70 wo endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and their corresponding knockout controls (Sirt1(Flox)/(Flox)). After 30-40 wk, Sirt1(endo-/)-animals exhibited diastolic dysfunction (DD), decreased mRNA expression of Serca2a in the LV, and decreased capillary density compared with control animals despite a similar VEGFa mRNA expression. However, LV fibrosis and hypoxia-inducible factor (HIF)1 alpha expression were not different. The creation of a transverse aortic constriction (TAC) provoked more severe DD and LV fibrosis in Sirt1(endo-/)-compared with control TAC animals. Although the VEGFa mRNA expression was not different and the protein expression of HIF1 alpha was higher in the Sirt1(endo-/)-TAC animals, capillary density remained reduced. In cultured endothelial cells administration of Sirtuin 1 inhibitor decreased mRNA expression of VEGF receptors FLT 1 and FLK 1. Ex vivo capillary sprouting from aortic explants showed impaired angiogenic response to VEGF in the Sirt1(endo-/-) mice. In conclusion, the data demonstrate 1) a defect in angiogenesis preceding development of DD; 2) dispensability of endothelial Sirtuin 1 under unstressed conditions and during normal aging; and 3) impaired angiogenic adaptation and aggravated DD in Sirt1(endo-/-) mice challenged with LV overload.