Sirt1: Role Under the Condition of Ischemia/Hypoxia

Abstract

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, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia.

Keywords: Aging; Apoptosis; Deacetylase; Ischemia/hypoxia; Oxidative stress; Sirt1.

Fig. 1

Molecular mechanisms of Sirt1–Foxos under the condition of ischemia/hypoxia. CR/Res/IPC suppresses the activation of PI3K/Akt, then alleviates the inhibition of PI3K/Akt on Foxos. Consistently, Sirt1 could deacetylate Foxos and promote its activation. The activated Foxos in nuclear regulates its downstream targets including MnSOD, Rab7, Bnip3, p27Kip1, and BIM, which could regulate the processes of autophagy, apoptosis, and cell cycle arrest in ischemia/hypoxia

Fig. 2

Complex interplay between Sirt1 and its downstream targets under ischemia/hypoxia condition. In ischemia/hypoxia, cellular NAD is depleted because of the NAD-consuming poly (ADP-ribose) polymerase (PARP)-1 overactivation, the mitochondrial permeability transition pore (mPTP) opening, and the downregulation of nicotinamide phosphoribosyltransferase (Nampt, a rate-limiting enzyme in the NAD+ synthesis salvage pathway), which lead to the decreased activation of Sirt1. In ischemia/hypoxia, the deacetylation function of Sirt1 is depleted, which leads to the acetylation of its downstream targets. a Ac-Foxos downregulates the Bnip3, p27Kip1, and Rab7 and upregulates Bim, which cause the cellular apoptosis and inhibition of autophagy and cell cycle arrest. b NF-κB pathway is activated with the inactivation of Sirt1. NF-κB upregulates the expression of iNOS and NO which lead to severe inflammation. c Inactivation of Sirt1 could suppress HIF-2α-directed production of erythropoietin (EPO) in hypoxic conditions, which lead to lack of oxygen supply and cell apoptosis. d, e Downregulation of Sirt1 activates the expression of PGC-1α and UCP2. The activated PGC-1α and UCP2 promote ROS and inhibit MnSOD which leads to high level of oxidative stress. f Ac-p53 in nucleus could upregulate the pro-apoptotic target Bax and lead to apoptosis in the end