SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

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.

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

“…Sirtuins have been implicated in glucose and lipid metabolism with an important role in various cellular metabolic pathways [40,41]. Recent studies have suggested a molecular interplay between HO-1 and sirtuin1 (SIRT1), demonstrating that upregulated expression of HO-1 activity can rescue SIRT1 expression, where the two form a "cytoprotective module" in a model of obesity [35].…”

“…The modulatory mediators of RAS, such as angiotensin II (AngII), increases cellular heme levels by peroxynitrite inactivation, produces excessive ROS and increases the release of inflammatory cytokines while decreasing expression of HO-1 and suppressing SIRT1. This redox imbalance leads to dyslipidemia and insulin resistance [40,41,52,53]. Heme increases lipid accumulation, promotes cell enlargement, induces over-expression of adipogenic genes, such as PPARG, C/EBP-α and adipocyte protein 2 (aP2), and downregulates adiponectin [32,34,54].…”

Targeting anti‐aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis

“…Alzheimer's disease 27,37 Huntington's disease, amyotrophic lateral sclerosis and spinal, bulbar muscular atrophy 37 Parkinson's disease 27 Cardiovascular diseases 20 Type-2 diabetes 20,27 that Sirt1 expressions can be a probable diagnostic tool for the detection of COPD. 59 The premature aging of the lungs results in lung inflammation, which causes cellular senescence.…”

“…Sirtuins, initially discovered in the late1980s, are universally known as a NAD‐dependent histone deacetylases that play a complex role in the process of aging. Sirtuins are also classified as antiaging molecules; emerging sources of evidence have shown that these highly conserved enzymes play a pivotal role in pulmonary fibrosis . Sirtuins are also known as modulators involved in DNA repair, energy metabolism, apoptosis, and oxidative stress responses .…”

“…All the seven members possess distinct activity, target, and tissue specificity but have a common NAD+ binding site. [20][21][22]24,36 There are four classified groups of Sirtuins: group I, to which Sirt1-Sirt3 belongs; group II, to which Sirt4 belongs; group III, which comprises of Sirt5; and group IV, to which Sirt6 and Sirt7 belong. Different members of the Sirtuin family possess different localizations ( Figure 1).…”