The Role of Sirtuin-1 in Cardiovascular and Renal Pathophysiology

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This Research Topic is part of The Role of Sirtuin-1 in Cardiovascular and Renal Pathophysiology series:
The Role of Sirtuin-1 in Cardiovascular and Renal Pathophysiology, Volume II

Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, leading to the regulation of plethora of physiological functions. SIRT1 mediates renoprotection through pathways that inhibit cell apoptosis, oxidative stress, autophagy, inflammation and fibrosis, and it also regulates lipid metabolism, blood pressure and sodium balance. Endothelial nitric oxide synthase (eNOS) also serves as a direct de-acetylation target for SIRT1, in a way that SIRT1 enhances eNOS activity and promotes endothelial NO-dependent vasodilation. In addition, SIRT1 has been shown to inhibit angiotensin II-induced hypertension by suppressing the expression of angiotensin II type 1 receptor (AT1R), and to protect the arterial wall from aortic aneurysm, atherosclerosis and ligation-induced remodeling, in part, by suppressing NFkB and TGF. Moreover, SIRT1 has been found to regulate cardiac function, by deacetylating ion channels and mitochondrial proteins, in cardiac myocytes. All this evidence supports a crucial role of SIRT1 in cardiovascular and renal homeostasis.

The catalytic activity of SIRT1 is intrinsically linked to the energy status of the cell. Changes in energy status, i.e. NAD+: NADH ratio, could influence the activity of SIRT1. In energy excess conditions such as high-fat diets, SIRT1 activity was reduced because of the decreased NAD+:NADH ratio. Conversely a low-energy status such as nutrient deprivation or exercise could enhance SIRT1 activity by increasing the NAD+:NADH ratio. Therefore, SIRT1, is an intracellular energy sensor which detects the concentration of intracellular NAD(+), and uses this information to adapt cellular energy output to cellular energy requirements and to regulate the mammalian metabolic clock. Therefore, SIRT1 might constitute a functional link between metabolic activity and genome stability and thus SIRT1 is likely to play important roles in renal and cardiovascular aging.

A link between SIRT1 and oxidative stress has been established in a variety of tissues. SIRT1 expression has been shown to boost the cellular anti-oxidant defense, in part via deacetylation and subsequent activation of the anti-oxidant transcription factor Nrf2 and protein p66shc. SIRT1 has also been found to regulate the activity and/or expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, FOXO family, and p53. These transcriptional factors are all known to be involved in the regulation of antioxidant enzyme expression, in addition to cell growth and apoptosis. This evidence suggests a protective role of SIRT-1 in cardiovascular and renal pathologies associated to oxidative stress

In addition to endogenous factors, SIRT1 can be pharmacologically activated or inhibited. Resveratrol, a polyphenolic compound, has been widely referred to as the SIRT1 activator . More recently synthetic non-polyphenolic SIRT1 activators, endowed with improved bioavailability, have been developed. Based on biological actions of SIRT1, these compounds may potentially become powerful tools for preventing the onset or progression of renal and cardiovascular dysfunction.

In this Research Topic we welcome original research articles, reviews or mini reviews evaluating the role of Sirtuin-1 in cell homeostasis as a defense mechanism in regulate cell signaling. These should primarily be focused on cardiovascular and renal functions, from basic to translational research. This Research Topic will provide a foundation for a more in depth understanding on the latest research on SIRT1 -1 biology, mechanisms of regulation, interactions with other cell pathways, and conditions of activation or inhibition of SIRT1. It will also highlight the protective functions of sirtuins in general (with a particular focus on SIRT-1), on the pathophysiology of renal and cardiovascular diseases.

Keywords: Sirtuin-1, antioxidant defense, inflammation, metabolism, aging, cardiovascular and renal function.

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