Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1–SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD+)-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Is...

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SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

Background:Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatmen...

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.

Cardiovascular disease (CVD) due to atherosclerosis is the main cause of death in both the elderly and patients with metabolic diseases, including diabetes. Aging processes contribute to the pathogenesis of atherosclerosis. Calorie restriction (CR) is recognized as a dietary intervention for promoting longevity and delaying age-related diseases, including atherosclerosis. Sirt1, an NAD+-dependent deacetylase, is considered an anti-aging molecule and is induced during CR. Sirt1 deacetylates target proteins and is linked to cellular metabolism, the redox state and survival pathways. Sirt1 expression/activation is decreased in vascular tissue undergoing senescence. Sirt1 deficiency in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and monocytes/macrophages contributes to increased oxidative stress, inflammation, foam cell formation, senescences impaired nitric oxide production and autophagy, thereby promoting vascular aging and atherosclerosis. Endothelial dysfunction, activation of monocytes/macrophages, and the functional and phenotypical plasticity of VSMCs are critically implicated in the pathogenesis of atherosclerosis through multiple mechanisms. Therefore, the activation of Sirt1 in vascular tissue, which includes ECs, monocytes/macrophages and VSMCs, may be a new therapeutic strategy against atherosclerosis and the increasing resistance to the metabolic disorder-related causal factors of CVD. In this review, we discuss the protective role of Sirt1 in the pathophysiology of vascular aging and atherosclerosis.

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The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis.

Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming.

As one of the main risk factors for cardiovascular diseases, ageing plays an important role in the alterations of vascular structure and function. Early vascular ageing refers to a condition in patients with impaired endothelial function and increased arterial stiffness that can be assessed before the overt clinical manifestations, such as hypertension and atherosclerosis. Both epidemiological and experimental data indicate that the biological age of endothelial cells in patients with cardiovascular diseases is older than their chronological age. In fact, endothelial senescence is present at the early stage of vascular ageing and contributes to the development of endothelial dysfunction and arterial stiffness. Sirtuin 1 (SIRT1), the mammalian ortholog of yeast longevity regulator Sir2, is a nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase that elicits a variety of vasoprotective functions. Overexpression of SIRT1 in endothelium prevents cellular senescence, enhances vasodilatory responses, and attenuates ageing-induced vascular damages. The present review summarizes the recent progresses related to SIRT1-mediated beneficial effects on the prevention of early vascular ageing and discusses the potential of SIRT1 in endothelial cells as an antivascular ageing target.

SIRT1 in Endothelial Cells as a Novel Target for the Prevention of Early Vascular Aging.

// Bo Bai 1,3,* , Andy W.C. Man 1,* , Kangmin Yang 1 , Yumeng Guo 1 , Cheng Xu 1 , Hung-Fat Tse 2 , Weiping Han 3 , Maria Bloksgaard 4 , Jo G.R. De Mey 4 , Paul M. Vanhoutte 1 , Aimin Xu 1,2 and Yu Wang 1 1 State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China 2 Department of Medicine, The University of Hong Kong, Hong Kong, China 3 Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore 4 Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark * Co-first authors Correspondence to: Yu Wang, email: // Keywords : hypertension, blood vessel remodeling, endothelial senescence, SIRT1, LKB1, Gerotarget Received : February 29, 2016 Accepted : May 23, 2016 Published : May 29, 2016 Abstract Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing. Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control. Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.

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Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

Aims Aged arteries are characterized by attenuated vasodilator and enhanced vasoconstrictor responses, which contribute to the development of diseases such as arterial hypertension, atherosclerosis, and heart failure SIRT1 is a longevity regulator exerting protective functions against vascular ageing, although the underlying mechanisms remain largely unknown This study was designed to elucidate the signalling pathways involved in endothelial SIRT1-mediated vasodilator responses in the arteries of young and old mice In particular, the contributions of nitric oxide (NO), endothelial NO synthase (eNOS), cyclooxygenase (COX), and/or soluble guanylyl cyclase (sGC) were examined Methods and results Wild type (WT) or eNOS knockout (eKO) mice were cross-bred with those overexpressing human SIRT1 selectively in the vascular endothelium (EC-SIRT1) Arteries were collected from the four groups of mice (WT, EC-SIRT1, eKO, and eKO-SIRT1) to measure isometric relaxations/contractions in response to various pharmacological agents Reduction of NO bioavailability, hyper-activation of COX signalling, and down-regulation of sGC collectively contributed to the decreased vasodilator and increased vasoconstrictor responses in arteries of old WT mice Overexpression of endothelial SIRT1 did not block the reduction in NO bioavailability but attenuated the hyper-activation of COX-2, thus protecting mice from age-induced vasoconstrictor responses in arteries of EC-SIRT1 mice Deficiency of eNOS did not affect endothelial SIRT1-mediated anti-contractile activities in arteries of eKO-SIRT1 mice Mechanistic studies revealed that overexpression of endothelial SIRT1 enhanced Notch signalling to up-regulate sGCβ1 in smooth muscle cells Increased expression and activity of sGC prevented age-induced hyper-activation of COX-2 as well as the conversion of endothelium-dependent relaxations to contractions in arteries of EC-SIRT1 mice Conclusion Age-induced down-regulation of sGC and up-regulation of COX-2 in arteries are at least partly attributable to the loss-of-endothelial SIRT1 function Enhancing the endothelial expression and function of SIRT1 prevents early vascular ageing and maintains vasodilator responses, thus representing promising drug targets for cardiovascular diseases

Endothelial SIRT1 prevents age-induced impairment of vasodilator responses by enhancing the expression and activity of soluble guanylyl cyclase in smooth muscle cells.

Unhealthy diet especially high-fat diet (HFD) is the major cause of hyperlipidemia leading to deterioration of chronic kidney diseases (CKD) in patients. Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin. Our previous clinical study demonstrated that the elevation of TMAO was positively correlated with CKD progression. Finasteride, a competitive and specific inhibitor of type II 5a-reductase, has been reported recently to be able to downregulate plasma TMAO level thus preventing the onset of atherosclerosis by our research group. In this study, we established a protein-overload nephropathy CKD mouse model by bovine serum albumin (BSA) injection to investigate whether hyperlipidemia could accelerate CKD progression and the underlying mechanisms. Finasteride was administrated to explore its potential therapeutic effects. The results of biochemical analyses and pathological examination showed that HFD-induced hyperlipidemia led to aggravated protein-overload nephropathy in mice along with an elevated level of circulating TMAO, which can be alleviated by finasteride treatment possibly through inhibition of Fmo3 in liver. The 16 S rRNA sequencing results indicated that HFD feeding altered the composition and distribution of gut microbiota in CKD mice contributing to the enhanced level of TMAO precursor TMA, while finasteride could exert beneficial effects via promoting the abundance of Alistipes_senegalensis and Akkermansia_muciniphila. Immunofluorescence staining (IF) and qRT-PCR results demonstrated the disruption of intestinal barrier by decreased expression of tight junction proteins including Claudin-1 and Zo-1 in HFD-fed CKD mice, which can be rescued by finasteride treatment. Cytokine arrays and redox status analyses revealed an upregulated inflammatory level and oxidative stress after HFD feeding in CKO mice, and finasteride-treatment could alleviate these lesions. To summarize, our study suggested that finasteride could alleviate HFD-associated deterioration of protein-overload nephropathy in mice by inhibition of TMAO synthesis and regulation of gut microbiota.

Yumeng Guo

Papers

SIRT1 in Endothelial Cells as a Novel Target for the Prevention of Early Vascular Aging.

Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

Endothelial SIRT1 prevents age-induced impairment of vasodilator responses by enhancing the expression and activity of soluble guanylyl cyclase in smooth muscle cells.

Finasteride Alleviates High Fat Associated Protein-Overload Nephropathy by Inhibiting Trimethylamine N-Oxide Synthesis and Regulating Gut Microbiota

Impact of climate warming on population mortality in South China