Endothelial SIRT1 in arterial remodeling and blood pressure control

Abstract

Ageing is associated with significant structural and functional alterations in the arterial wall. Aged arteries are characterized by augmented stiffness and reduced compliance due to the accumulation of extracellular matrix and activation of vascular smooth muscle cells. The remodeling of large arteries contributes to the elevation of blood pressure and increased risk of cardiovascular diseases. Vascular endothelium plays an important role in arterial remodeling by sensing haemodynamic changes, in turn releasing vasoactive autacoids such as nitric oxide (NO). SIRT1 is a NAD-dependent protein deacetylase with anti-aging and vasoprotective properties. Previous results demonstrated that SIRT1 prevents endothelial senescence by targeting LKB1, a serine/threonine protein kinase. The present project investigated the role of endothelial SIRT1 in vascular remodeling and blood pressure control using genetically modified mice models. First, experiments were performed in mice deficient with endothelial NO synthase (eNOS), with or without endothelial overexpression of human SIRT1. In eNOS-deficient mice, the augmented blood pressure was associated with adverse arterial remodeling and stiffening, as demonstrated by the increased cellularity and collagen deposition in the blood vessel wall. Overexpression of SIRT1 in endothelial cells attenuated the augmented blood pressure and adverse arterial remodeling. Mechanistically, SIRT1 inhibited LKB1 protein binding to the promoter of transforming growth factor beta 1 (TGFb1), a potent modulator of arterial remodeling, thus preventing the activation and proliferation of smooth muscle cells. HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2) is a giant protein involved in DNA damage repair. Here, the study identified the protein complex formed between HERC2, SIRT1 and LKB1, which was crucial in modulating endothelial function, in turn affecting the proliferation and activation of vascular smooth muscle cells as well as arterial remodeling. Moreover, the HERC2/SIRT1/LKB1 signaling axis was negatively regulated by ring finger protein 8 [RNF8, a binding protein of HERC2 for repairing DNA damages], ubiquitination or poly-ADPribosylation, as well as the intracellular levels of acetyl-CoA. The protective role of SIRT1 in vascular endothelial cells on Per2 mutation-induced vascular and metabolic abnormalities. The results demonstrated that overexpression of endothelial SIRT1 prevented the loss of dipping of diurnal blood pressure and the development of hypertension in Per2-mutant mice. The premature metabolic ageing phenotype caused by Per2 mutation, including decreased skeletal muscle mass and increased fat mass was also prevented by endothelial overexpression of SIRT1. In addition, Per2-mutant mice also showed increase in diurnal activity and food consumption as well as augmented circulating branched chain amino acids (BCAA). Endothelial SIRT1 elicits the anti-vascular and metabolic ageing activities via modulating amino acid metabolism. The results collectively suggest that SIRT1 in endothelial cells plays an important role in modulating the remodeling process of arteries by targeting LKB1-mediated TGFb1 expression and facilitating protein complex formation with HERC2 and LKB1. This signaling axis is tightly controlled by various feedback mechanisms. Endothelial SIRT1 also facilitated the coordination and crosstalks between systemic energy homeostasis, circadian rhythm and vascular function via regulating amino acid metabolism. In summary, the findings support endothelial SIRT1 as a potential anti-vascular and metabolic ageing drug target for therapeutic development in cardiovascular and metabolic diseases.