Your browser doesn't support javascript.
loading
Role of Argininosuccinate Synthase 1 -Dependent L-Arginine Biosynthesis in the Protective Effect of Endothelial Sirtuin 3 Against Atherosclerosis.
Cao, Xiaoyun; Wu, Vivian Wei Yan; Han, Yumeng; Hong, Huiling; Wu, Yalan; Kong, Alice Pik Shan; Lui, Kathy O; Tian, Xiao Yu.
Afiliação
  • Cao X; School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Wu VWY; Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Han Y; School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Hong H; School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Wu Y; School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Kong APS; School of Biomedical Sciences, Heart and Vascular Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
  • Lui KO; Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha, 410013, China.
  • Tian XY; Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong SAR, 999077, China.
Adv Sci (Weinh) ; 11(12): e2307256, 2024 Mar.
Article em En | MEDLINE | ID: mdl-38233193
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.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Sirtuína 3 Limite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Sirtuína 3 Limite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China