The Role of Sirtuin1 in Regulating Endothelial Function, Arterial Remodeling and Vascular Aging

Abstract

Sirtuin1 (SIRT1), which belongs to a highly conserved family of protein deacetylase, is one of the best-studied sirtuins. SIRT1 is involved in a variety of biological processes, including energy metabolism, cell proliferation and survival, chromatin dynamics, and DNA repair. In the vasculature, SIRT1 is ubiquitously expressed in endothelial cells, smooth muscle cells, and perivascular adipose tissues (PVAT). Endothelial SIRT1 plays a unique role in vasoprotection by regulating a large variety of proteins, including endothelial nitric oxide synthase (eNOS). In endothelial cells, SIRT1 and eNOS regulate each other synergistically through positive feedback mechanisms for the maintenance of endothelial function. Recent studies have shown that SIRT1 plays a vital role in modulating PVAT function, arterial remodeling, and vascular aging. In the present article, we summarize recent findings, review the molecular mechanisms and the potential of SIRT1 as a therapeutic target for the treatment of vascular diseases, and discuss future research directions.

Keywords: PVAT; SIRT1; eNOS; vascular aging; vascular remodeling.

FIGURE 1

Crosstalk between endothelial SIRT1 and eNOS in mediating endothelial function. Schematic presentation of the current idea on the reciprocal regulation of SIRT1 and eNOS. Resveratrol activates both SIRT1 and eNOS, whereas FOXO1 and FOXO3a are involved in the resveratrol induced eNOS transcriptional activation, based on the published literature (Xia et al., 2013). Cilostazol increases NO production by stimulating eNOS serine 1177 phosphorylation mediated by cAMP/PKA- and PI3K/Akt-dependent pathways. NO, nitric oxide; FOXO, forkhead box O; SMC, smooth muscle cells. KLF2, Krüppel-like Factor 2.

FIGURE 2

Pathways implicating the development of arterial remodeling and the role of SIRT1 in targeting arterial remodeling. Arterial remodeling is the structural alteration of arteries resulting from endothelial senescence/dysfunction, SMC activation, and changes in the extracellular matrix. Based on the current limited literature, SIRT1 in vascular smooth muscle cells is responsible for repressing neointima formation via a p53-PAI-1 pathway and inhibits Ang-II induced remodeling and intimal thickening. SIRT1 in vascular smooth muscle cells also prevents arterial stiffening via inhibition of NF-κB and downregulation VCAM-1 and p47phox. Endothelial SIRT1 facilitates protein complex formation with HERC2 and LKB1, which in turn, enhances LKB1 degradation and downregulation of TGFβ-signaling. SIRT1-HERC2-LKB1 axis prevents arterial remodeling by targeting endothelial senescence and SMC activation. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells. VCAM-1, vascular cell adhesion protein 1. AngII, angiotensin II. MMP, matrix metalloproteinase. PAI-1, plasminogen activator inhibitor-1. TGFβ, transforming growth factor-beta. NO, nitric oxide. PDGF, platelet-derived growth factor. HERC2, HECT and RLD domain containing E3 ubiquitin-protein ligase 2.

FIGURE 3

Role of SIRT1 in modulating PVAT function. PVAT is critical in modulating vascular function. Crataegus extract WS^® 1442 activates SIRT1 via increased NAD⁺ production by NAMPT. WS^® 1442 prevents PVAT dysfunction via reversing the reduced phosphorylation and enhanced acetylation of PVAT eNOS caused by HFD feeding. SIRT1 ameliorates PVAT dysfunction caused by NFκB activation and PVAT inflammation fructose (Chen et al., 2016) or HFD (Sun et al., 2014). SIRT1 also increases mitochondrial biogenesis via PGC-1α. NO, nitric oxide. HFD, high-fat diet. PGC-1α, peroxisome proliferator-activated receptor-gamma and coactivator-1 alpha. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells. NAMPT, nicotinamide phosphoribosyltransferase. AMPK, 5′ AMP-activated protein kinase.

FIGURE 4

Aging-induced SIRT1 downregulation in endothelial cells and PVAT. During aging, SIRT1 expression and activity are reduced in senescent endothelial cells. Downstream targets of SIRT1, including sGC, p53, LKB1, and PGC-1α, are altered leading to endothelial senescence. In contrast, senescent endothelial cells have lower levels of eNOS activity and reduced levels of NO production. Mitochondrial dysfunction in PVAT can lead to PVAT senescence resulting in the loss of its anticontractile properties. The endothelial senescence, together with PVAT senescence, lead to vascular aging, causing increased cardiovascular risk. sGC, soluble guanylyl cyclase. cGMP, cyclic guanosine monophosphate. LKB1, liver kinase b1, AMPK, 5′ AMP-activated protein kinase. PGC-1α, peroxisome proliferator-activated receptor-gamma and coactivator-1 alpha. PPARα, peroxisome proliferator-activated receptor alpha. MR, mineralocorticoid receptor. ROS, reactive oxidative species.