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

Bai, Bo; Man, Andy W C; Yang, Keli; Guo, Yumeng; Xu, Cheng; Tse, Hung‐Fat; Han, Weiping; Bloksgaard, Maria; Mey, Jo G. R. De; Vanhoutte, Paul M.; Xu, Aimin; Wang, Yu

doi:10.18632/oncotarget.9687

Cited by 41 publications

(42 citation statements)

References 55 publications

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“…41 Additionally, an in vitro deacetylation assay also showed that SIRT1 seemed not to deacetylate LKB1 peptide containing acetylated lysine 48. 42 SIRT1 may regulate AMPK by other mechanisms. For instance, SIRT1 regulates secretion of adipokines such as adiponectin, 43 which activates AMPK through a CaMKKβ-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

et al. 2017

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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 treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. Methods Male C57BL/6J wild-type (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/day for four weeks) in male C57BL/6J Sirt2-KO mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice and their respective littermates (8~12-week-old). Metformin (200 mg/kg/day) was used to treat WT and Sirt2-KO mice that were infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results SIRT2 protein expression levels were down-regulated in hypertrophic hearts from mice. Sirt2-KO markedly exaggerated cardiac hypertrophy and fibrosis as well as decreases in cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. Conclusions SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

et al. 2017

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“…More recently, another molecular mechanism underlying the preventive effect of SIRT1 against endothelial senescence and vascular aging has been demonstrated, showing that SIRT1 prevents endothelial senescence by downregulating acetylation of stress-responsive serine/threonine liver kinase B1 (LKB1) via HERC2, a giant scaffold protein, and E3 ubiquitin ligase (Fig. 3) (13). In aged arteries or senescent ECs, an increased nuclear accumulation of acetylated LKB1 is observed when SIRT1 expression and function are lost with concomitant irreversible alterations of vascular stiffness, blood vessel wall, and adverse arterial remodeling, suggesting that the SIRT1/HERC2/LKB1 complex fine tunes the crosstalk between endothelial and VSMCs to maintain vascular homeostasis (13).…”

Section: Sirt1 In Cell Senescence and Aging Processesmentioning

confidence: 99%

“…3) (13). In aged arteries or senescent ECs, an increased nuclear accumulation of acetylated LKB1 is observed when SIRT1 expression and function are lost with concomitant irreversible alterations of vascular stiffness, blood vessel wall, and adverse arterial remodeling, suggesting that the SIRT1/HERC2/LKB1 complex fine tunes the crosstalk between endothelial and VSMCs to maintain vascular homeostasis (13). Conversely, SIRT1 overexpression and increased LKB1deacetylation prevented the EC senescence in vitro, as well as the stress-induced senescence in mice (221).…”

Section: Sirt1 In Cell Senescence and Aging Processesmentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

295

238

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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 Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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“…Donato et al previously reported that Sirt1 expression is reduced in endothelial cells obtained from arteries of older human adults (64 ± 1 years) compared to those from younger adults (25 ± 1 years), and reduced endothelial Sirt1 expression with aging may be related to endothelial dysfunction through the impairment of NO production from eNOS [47]. Recently, Bai et al demonstrated the molecular mechanisms underlying the preventive effect of endothelial senescence and vascular aging [48]. Sirt1 prevents endothelial senescence by enhancing Liver kinase B1 (LKB1) degradation by its deacetylation, which causes an interaction with HECT and RLD domain containing E3 ubiquitin protein ligase 2(HERC2), a giant scaffolding protein and E3 ubiquitin ligase.…”

Section: Introductionmentioning

confidence: 99%

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

Kitada

Ogura

Koya

2016

Aging

216

149

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

Cited by 41 publications

References 55 publications

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

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

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