Abstract
Sirtuin-1 (SirT1) is a nicotinamide adenine dinucleotide-dependent deacetylase and the best characterized member of the sirtuins family in mammalians. Sirtuin-1 shuttles between the cytoplasm and the nucleus, where it deacetylates histones and non-histone proteins involved in a plethora of cellular processes, including survival, growth, metabolism, senescence, and stress resistance. In this brief review, we summarize the current knowledge on the anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-senescence effects of SirT1 with an emphasis on vascular diseases. Specifically, we describe recent research advances on SirT1-mediated molecular mechanisms in aortic aneurysm (AA), and how these processes relate to oxidant stress and the heme-oxygenase (HO) system. HO-1 and HO-2 catalyze the rate-limiting step of cellular heme degradation and, similar to SirT1, HO-1 exerts beneficial effects in the vasculature through the activation of anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-proliferative signaling pathways. SirT1 and HO-1 are part of an integrated system for cellular stress tolerance, and may positively interact to regulate vascular function. We further discuss sex differences in HO-1 and SirT1 activity or expression, and the potential interactions between the two proteins, in relation to the progression and severity of AA, as well as the ongoing efforts for translational applications of SirT1 activation and HO-1 induction in the treatment of cardiovascular diseases including AA.
Highlights
Sirtuin-1 shuttles between the cytoplasm and the nucleus, where it deacetylates histones and nonhistone proteins involved in a plethora of cellular processes, including survival, growth, metabolism, senescence, and stress resistance
Activation of nuclear factor kB (NF-kB) and p53 promotes inflammation, apoptosis, senescence, and oxidant stress in animal models of aortic aneurysm (AA; Gomez et al, 2013; Leeper et al, 2013; Chen et al, 2016; Moran et al, 2017) while activation of FOXOs and peroxisome proliferator-activated receptor-γ co-activator1α (PPARγ) reverses these processes by opposing pro-inflammatory and apoptotic factors in animal and human studies (Jones et al, 2009; Oellerich and Potente, 2012; Radak et al, 2013; Motoki et al, 2015; Tai et al, 2016; Lu et al, 2020)
We have recently shown that mice with vascular smooth muscle (VSM)-specific deletion of SirT1 have a drastically increased mortality (70%) in response to angiotensin II (angII) infusion due to aortic wall dissection, in the thoracic region, which resulted from excess oxidant production and oxidantstimulated matrix metalloproteinases (MMPs) activation (Fry et al, 2015)
Summary
We have recently shown that mice with VSM-specific deletion of SirT1 have a drastically increased mortality (70%) in response to angII infusion due to aortic wall dissection, in the thoracic region, which resulted from excess oxidant production and oxidantstimulated matrix metalloproteinases (MMPs) activation (Fry et al, 2015). Endothelial and VSM SirT1 are known to regulate the cellular redox state in the vascular wall by multiple mechanisms, including direct deacetylation of FOXOs, NF-kB, Nrf2, mitochondrial superoxide dismutase and Nox, which overall decrease ROS production (Fry et al, 2015; Huang et al, 2015; Zhang et al, 2017).
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