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

Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

doi:10.18632/aging.101068

Cited by 172 publications

(130 citation statements)

References 110 publications

(132 reference statements)

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“…Increased calcineurin/NFAT signalling in the diseased human and mouse myocardium reactivates the transcription factor Hand2 and fetal gene program, intricately linked to pathological heart disease (38). Previous reports have shown that SIRT1, a founding member of Sirtuins, suppresses NFAT activity during inflammation in atherosclerosis (39,40). Similarly, SIRT3, a mitochondrial deacetylase deficiency in cardiomyocytes is known to upregulate the activity of NFAT (41).…”

Section: Discussionmentioning

confidence: 99%

SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

Sarikhani

Maity

Mishra

et al. 2018

Journal of Biological Chemistry

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Heart failure is an aging-associated disease, which is the leading cause of death worldwide. Sirtuin family members have been largely studied in the context of aging and agingassociated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD + -dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating NFAT transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart. SIRT2 deficient mice develops spontaneous pathological cardiac hypertrophy, remodelling, fibrosis and dysfunction in an age-dependent manner. Moreover, young SIRT2 deficient mice develops exacerbated agonist-induced hypertrophy. On contrast, SIRT2 overexpression attenuated agonist-induced cardiac hypertrophy in cardiomyocytes in a cell autonomous manner. Mechanistically, SIRT2 binds to and deacetylates NFATc2 transcription factor. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear localization of NFATc2, resulting in increased transcription activity. Our results suggest that inhibition of NFAT rescues the cardiac dysfunction in SIRT2 deficient mice. Thus, our study establishes SIRT2 as a novel endogenous negative regulator of NFAT transcription factor. _____________________________________

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Section: Discussionmentioning

confidence: 99%

SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

Sarikhani

Maity

Mishra

et al. 2018

Journal of Biological Chemistry

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“…Atheroclerosis is promoted by SIRT1 deficiency in ECs, VSMCs, and monocyte/macrophages, which actively mediates oxidative stress, inflammation, foam cell formation, and impaired autophagy in vascular wall (93). In this regard, severe autophagy stimulated by high inflammation or oxidative stress leads to reduced collagen synthesis, fibrous cap thinning, plaque destabilization, restenosis, and acute coronary syndrome.…”

Section: Protective Role Of Sirt1 and Sirt6 In Atherosclerosismentioning

confidence: 99%

“…SIRT1 exerts an atheroprotective effect by increasing NO production, HERC2-mediated degradation of LKB1, blocking the NF-jB-mediated inflammatory process, reducing oxidative stress, and controlling autophagy (93,204). In apolipoprotein E knock-out (ApoE -/-) mice, the impaired endothelium-dependent vasorelaxation was improved in SIRT1-transgenic mice and accompanied by aortic eNOS upregulation (8,214) (Fig.…”

Section: Sirt1 and Atherosclerosismentioning

confidence: 99%

“…Intriguing is the role of sirtuins in vascular homeostasis and cardiovascular disease (CVD), as they, all expressed at vascular level, take part in the normal and diseased blood vessel processes (42,78,93,195). In endothelial cells (ECs), SIRT1 uniquely regulates cell physiology by controlling endothelial homeostasis and vascular functionality by modulating endothelial nitric oxide synthase (eNOS) activity, p53, angiotensin II (Ang II) type 1 receptor (AT1R), and forkhead box O (FOXO) 1.…”

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confidence: 99%

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SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D'Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

213

183

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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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“…Premature and segmental activation of aging may contribute, among other pathologies, to autoimmunity [4], vascular abnormalities [5, 6], and fibrosis [7–17]. It is therefore not surprising that scleroderma, or systemic sclerosis (SSc), a disease characterized by the triad of autoimmune activation, vasculopathy, and fibrosis, has been described as a disease of accelerated aging [17].…”

Section: Introductionmentioning

confidence: 99%

Sirtuins and Accelerated Aging in Scleroderma

Wyman

Atamas

2018

Curr Rheumatol Rep

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Purpose of Review Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms. Recent Findings Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Summary Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

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

Cited by 172 publications

References 110 publications

SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

Sirtuins and Accelerated Aging in Scleroderma

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