PDF(Pubmed)
Abstract：
Atherosclerosis is initiated with endothelial cell (EC) dysfunction and vascular inflammation under hyperlipidemia. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase. However, the specific role of endothelial SIRT3 during atherosclerosis remains poorly understood. The present study aims to study the role and mechanism of SIRT3 in EC function during atherosclerosis. Wild-type Sirt3f/f mice and endothelium-selective SIRT3 knockout Sirt3f/f; Cdh5Cre/+ (Sirt3EC-KO) mice are injected with adeno-associated virus (AAV) to overexpress PCSK9 and fed with high-cholesterol diet (HCD) for 12 weeks to induce atherosclerosis. Sirt3EC-KO mice exhibit increased atherosclerotic plaque formation, along with elevated macrophage infiltration, vascular inflammation, and reduced circulating L-arginine levels. In human ECs, SIRT3 inhibition resulted in heightened vascular inflammation, reduced nitric oxide (NO) production, increased reactive oxygen species (ROS), and diminished L-arginine levels. Silencing of SIRT3 results in hyperacetylation and deactivation of Argininosuccinate Synthase 1 (ASS1), a rate-limiting enzyme involved in L-arginine biosynthesis, and this effect is abolished in mutant ASS1. Furthermore, L-arginine supplementation attenuates enhanced plaque formation and vascular inflammation in Sirt3EC-KO mice. This study provides compelling evidence supporting the protective role of endothelial SIRT3 in atherosclerosis and also suggests a critical role of SIRT3-induced deacetylation of ASS1 by ECs for arginine synthesis.
摘要：
动脉粥样硬化起因于高脂血症下的内皮细胞(EC)功能障碍和血管炎症。Sirtuin3（SIRT3）是一种线粒体脱乙酰酶。然而,内皮细胞SIRT3在动脉粥样硬化过程中的具体作用尚不清楚.本研究旨在研究SIRT3在动脉粥样硬化过程中在EC功能中的作用及机制。野生型Sirt3f/f小鼠和内皮选择性SIRT3敲除Sirt3f/f;Cdh5Cre/+(Sirt3EC-KO)小鼠注射腺相关病毒(AAV)以过表达PCSK9,并饲喂高胆固醇饮食(HCD)12周以诱导动脉粥样硬化。Sirt3EC-KO小鼠表现出增加的动脉粥样硬化斑块形成，随着巨噬细胞浸润的增加，血管炎症,和降低循环L-精氨酸水平。在人类ECs中，SIRT3抑制导致血管炎症加剧，减少一氧化氮（NO）的产生，增加活性氧（ROS），和减少L-精氨酸水平。SIRT3的沉默会导致精氨酸琥珀酸合酶1（ASS1）的高乙酰化和失活，一种参与L-精氨酸生物合成的限速酶，这种效应在突变型ASS1中消失。此外，在Sirt3EC-KO小鼠中,L-精氨酸补充减弱增强的斑块形成和血管炎症。这项研究提供了令人信服的证据支持内皮SIRT3在动脉粥样硬化中的保护作用，并且还表明SIRT3诱导的ECs对ASS1的去乙酰化对精氨酸合成的关键作用。
