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Review
. 2018 Mar 10;28(8):711-732.
doi: 10.1089/ars.2017.7178. Epub 2017 Jun 29.

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

Nunzia D'Onofrio  1 , Luigi Servillo  1 , Maria Luisa Balestrieri  1
Affiliations
Review

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

Nunzia D'Onofrio et al. Antioxid Redox Signal. .

Abstract

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.

Keywords: SIRT1; SIRT6; cardiovascular disease; endothelial dysfunction; oxidative stress; vascular aging.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Mammalian sirtuins. Schematic representation of the seven members of sirtuin family with their catalytic activity and predominant subcellular localization.
<b>FIG. 2.</b>
FIG. 2.
SIRT1 and SIRT6 response to cellular redox status and oxidative stress. At vascular level, the physiological functions of SIRT1 and SIRT6 in the control of the cellular redox state are mediated by deacetylation of multiple targets, including histones, transcription factors (FOXO, NF-κB, p53, and Nrf2), and enzymes involved in the vascular protection. SIRT6, a highly specific histone type 3 (H3) deacetylase, targets acetylated Lys-9 (acH3K9), Lys-56 (acH3K56), and Lys-18 (acH3K18). However, oxidative stress associated with various vascular pathophysiological conditions impairs SIRT1 and SIRT6 activities on their specific targets (rectangle enclosed), resulting in a decreased vascular protection against oxidative stress. →, positive regulation; ˧, negative regulation. CAT, catalase, eNOS, endothelial nitric oxide synthase; FOXO, forkhead box O; GPx, glutathione peroxidase; iNOS, inducible nitric oxide synthase; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor-kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; PCAF, p300/CBP-associated factor; PPAR-α, peroxisome proliferator-activated receptor coactivator 1-α; SIRT, sirtuins.
<b>FIG. 3.</b>
FIG. 3.
SIRT1 and SIRT6 in vascular aging. Aging processes, by blocking all cellular signals controlled by SIRT1 and SIRT6 (circle enclosed), lead to vascular aging. SIRT1 and SIRT6 deacetylate their specific and common substrates, including histone and nonhistone molecules, thus improving genome stability and preventing cell senescence. SIRT1 regulates eNOS via transcriptional and post-transcriptional deacetylation, resulting in the NO-mediated vascular protection. SIRT1 and SIRT6 control inflammation by deacetylating the p65 subunit of NF-κB, thus inhibiting the expression of inflammation-related genes, including ICAM-1, as well as proinflammatory cytokines. In ECs, SIRT6 protects from senescence and oxidative stress by blocking p21Cip1/Waf1 signaling and sustaining high eNOS levels. The crosstalk between sirtuins and senescence-related proteins, such as p66Shc, prevents vascular diseases based on antioxidative stress responses. →, positive regulation; ˧, negative regulation. ECs, endothelial cells; ICAM-1, intercellular adhesion molecule-1.
<b>FIG. 4.</b>
FIG. 4.
SIRT1 and SIRT6 during altered glucose homeostasis. Hyperglycemia downregulates SIRT1- and SIRT6-controlled signaling pathways (rectangle enclosed). The diverse functions of SIRT1 and SIRT6 in nutrient sensing determine a fine adjustment of glucose homeostasis. →, positive regulation; ˧, negative regulation.
<b>FIG. 5.</b>
FIG. 5.
SIRT1 and SIRT6 protection in atherosclerosis. Molecular pathways controlled by SIRT1 and SIRT6 (triangle enclosed) allow the reduction of NF-κB activation, the oxLDL uptake by downregulation of Lox-1 expression, TG and hepatic cholesterol synthesis, and suppression of foam cell formation via deacetylation and subsequent activation of LXR. SIRT6 targets histone type 3 (H3) acetylated Lys-9 (acH3K9) and Lys-56 (acH3K56). →, positive regulation; ˧, negative regulation. Lox-1, lectin-like oxLDL receptor 1; LXR, liver X-receptor; oxLDL, oxidized low-density lipoproteins; TG, triglycerides.
<b>FIG. 6.</b>
FIG. 6.
SIRT1 and SIRT6 signaling networks in the heart protection. The diverse roles of SIRT1 and SIRT6 in the heart include protective effects against cardiac hypertrophy, I/R injury, oxidative stress injury, hearth failure, and autophagy. SIRT1 acts by deacetylating NF-κB, FOXO, and Akt. Similarly, SIRT1 protects cardiomyocytes from endoplasmic reticulum stress by deacetylating eIF2α on Lys-141 (K141) and Lys-143 (K143) residues. SIRT6-FOXO3 complex enhances the transcription of antioxidant genes, MnSOD and CAT. SIRT6 protects against hypoxic stress by activating AMPK, upregulating Bcl2, and suppressing the activity of NF-κB. SIRT6 blocks IGF-Akt signaling by targeting c-Jun and deacetylating histone type 3 (H3) acetylated Lys-9 (acH3K9). →, positive regulation; ˧, negative regulation. Bcl-2, B-cell lymphoma 2; eIF2α, eukaryotic translation initiation factor 2α; IGF, insulin-like growth factor; I/R, ischemia-reperfusion.
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