SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Xu, Suowen; Yin, Meimei; Koroleva, Marina; Mastrangelo, Michael A.; Zhang, Wenbo; Bai, Péter; Little, Peter J.; Jin, Zheng Gen

doi:10.18632/aging.100975

Cited by 86 publications

(65 citation statements)

References 70 publications

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“…Since Sirt6 plays a pivotal role in inflammation [12, 15, 20, 29, 30], we speculate that inflammation may also contribute to renal dysfunction in Sirt6 KO mice. Therefore we examined the role of Sirt6 in the renal inflammatory processes.…”

Section: Resultsmentioning

confidence: 99%

Sirt6 deficiency results in progression of glomerular injury in the kidney

Huang

Liu

Zhu

et al. 2017

Aging

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Aging is associated with an increased incidence and prevalence of renal glomerular diseases. Sirtuin (Sirt) 6, a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, has been shown to protect against multiple age-associated phenotypes; however it is unknown whether Sirt6 has a direct pathophysiologic role in the kidney. In the present study, we demonstrate that Sirt6 is expressed in the kidney and aging Sirt6-deficient mice exhibit renal hypertrophy with glomerular enlargement. Sirt6 deletion induces podocyte injury, including decreases in slit diaphragm proteins, foot process effacement, and cellular loss, resulting in proteinuria. Knockdown of Sirt6 in cultured primary murine podocytes induces shape changes with loss of process formation and cell apoptosis. Moreover, Sirt6 deficiency results in progressive renal inflammation and fibrosis. Collectively, these data provide compelling evidence that Sirt6 is important for podocyte homeostasis and maintenance of glomerular function, and warrant further investigation into the role of Sirt6 in age-associated kidney dysfunction.

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Section: Resultsmentioning

confidence: 99%

Sirt6 deficiency results in progression of glomerular injury in the kidney

Huang

Liu

Zhu

et al. 2017

Aging

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“…+/-/ApoE -/-mice fed a high-fat diet show impressive atherosclerotic lesion development, together with increased expression of the proinflammatory cytokine VCAM-1 (200).…”

Section: Sirt1 and Sirt6 In Cardiovascular Diseasementioning

confidence: 99%

“…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. Intriguingly, beside SIRT1, the link between SIRT6 and atherosclerotic plaque vulnerability has been unveiled only recently (16,44,110,200,218).…”

Section: Protective Role Of Sirt1 and Sirt6 In Atherosclerosismentioning

confidence: 99%

“…The direct involvement of SIRT6 in atherosclerotic plaque development emerged recently from ex vivo and in vivo evidence in diabetic patients and in animal models of atherosclerosis (16,110,200,218). Indeed, carotid atherosclerotic plaques from type 2 diabetic patients displayed reduced SIRT6 expression compared with plaques from nondiabetic patients (16).…”

Section: Sirt1 and Sirt6 In Cardiovascular Diseasementioning

confidence: 99%

“…SIRT4 and SIRT7 aggravate cardiac hypertrophy and negatively affect the proliferation and migration of ECs and vascular smooth muscle cells (VSMCs) (20,199). The cardioprotective role of SIRT1 and SIRT3 is common to SIRT6, a sirtuin only recently recognized to be involved in atherosclerotic plaque development (16,110,200,218). However, the dual role of SIRT6 and SIRT1 as tumor promoter and tumor suppressor in cancer indicates that multiple mechanisms, to date not fully unveiled, might underlie the epigenetic activity of these sirtuins (188).…”

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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

266

206

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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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New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation

Rizzo

Marfella

Cataldo

et al. 2020

Journal Cellular Physiology

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Conflicting data are reported on the relationship between hyperglycaemia, diabetes and SIRT6 expression. To elucidate hyperglycaemia-induced molecular mechanisms regulating SIRT6 expression, the effect of hyperglycaemia on DNA methylation and SIRT6 expression has been evaluated in human aortic endothelial cells exposed to high glucose. DNA methylation of SIRT6 and any potential clinical implication was also evaluated in type 2 diabetic patients and compared with healthy controls. Endothelial cells exposed to high glucose showed lower methylation levels in SIRT6 promoter and increased SIRT6 and TET2 expression. The high glucose-induced epigenetic changes persisted after 48 h of glucose normalization. Diabetic patients showed lower levels of SIRT6 DNA methylation compared with nondiabetic patients. SIRT6 DNA methylation levels inversely correlated with plasma glucose. Our results firstly demonstrate the involvement of epigenetic mechanisms in regulating SIRT6 expression. Further experiments are necessary to clarify metabolic memory mechanisms driving to diabetic complications and how SIRT6 is potentially involved.

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SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Cited by 86 publications

References 70 publications

Sirt6 deficiency results in progression of glomerular injury in the kidney

Sirt6 deficiency results in progression of glomerular injury in the kidney

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation

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