Sirtuins in vascular diseases: Emerging roles and therapeutic potential

Abstract

Silent information regulator-2 (Sir-2) proteins, or sirtuins, are a highly conserved protein family of histone deacetylases that promote longevity by mediating many of the beneficial effects of calorie restriction which extends life span and reduces the incidence of cancer, cardiovascular disease (CVD), and diabetes. Here, we review the role of sirtuins (SIRT1-7) in vascular homeostasis and diseases by providing an update on the latest knowledge about their roles in endothelial damage and vascular repair mechanisms. Among all sirtuins, in the light of the numerous functions reported on SIRT1 in the vascular system, herein we discuss its roles not only in the control of endothelial cells (EC) functionality but also in other cell types beyond EC, including endothelial progenitor cells (EPC), smooth muscle cells (SMC), and immune cells. Furthermore, we also provide an update on the growing field of compounds under clinical evaluation for the modulation of SIRT1 which, at the state of the art, represents the most promising target for the development of novel drugs against CVD, especially when concomitant with type 2 diabetes.

The role of SIRT6 in tumors

“…2,3 The vast effort of European investigators in standardizing MRD assessment by polymerase chain reaction (PCR) and flow cytometry merits recognition and credit. 4,5 At present, we have several independent quantitative monitoring strategies, namely, PCR on DNA targets, reverse transcription (RT)-PCR on abnormal ribonucleic acid (RNA) transcribed from fusion genes or overexpression of normal messenger (m)RNA, and flow cytometry. Their relative implications remain under investigation.…”

“…2 In mammalian cells, the Sirtuin family is composed of seven members that show different subcellular localization and functions (transcription, metabolism, fat mobilization, DNA repair, stress responses, apoptosis, tumorigenesis and aging), 3,4 and conserve the catalytic domain and the NAD + binding site. 5 In cancer and agingassociated pathways, SIRT6 is crucial since it prevents genomic instability, maintains telomere integrity, and regulates metabolic homeostasis and DNA repair. 6 SIRT6 can be considered a double-edged sword in cancer because of its dual role of both tumor suppressor and oncogene (Table 1).…”

Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

“…of the sirtuin family with multiple roles in the modulation of the vascular function. 11 Indeed, it is well known that SIRT1 prevents hydrogen peroxide-induced premature senescence of EC and protects blood vessels from hyperglycemia-induced endothelial dysfunction through a mechanism involving the downregulation of p66Shc expression. TMAO.…”

“…9,10 The hyperglycaemia-induced endothelial dysfunction is also mediated by downregulation of sirtuins, proteins that take part to the mechanisms regulating vascular dysfunction related to aging, inflammation, and diabetes. 11,12 At vascular level, the effects of sirtuin 1 (SIRT1) are due to the deacetylation of multiple targets, including endothelial nitric oxide synthase, peroxisome proliferator-activated receptor-γ coactivator 1-α, p53, forkhead Box O family, and nuclear factor-kappa B (NF-κB). 11,12 Sirtuin 6 (SIRT6) plays a key role in cardiac hypertrophy, heart failure, myocardial hypoxic damage, metabolism and endothelial inflammation.…”

“…11,12 At vascular level, the effects of sirtuin 1 (SIRT1) are due to the deacetylation of multiple targets, including endothelial nitric oxide synthase, peroxisome proliferator-activated receptor-γ coactivator 1-α, p53, forkhead Box O family, and nuclear factor-kappa B (NF-κB). 11,12 Sirtuin 6 (SIRT6) plays a key role in cardiac hypertrophy, heart failure, myocardial hypoxic damage, metabolism and endothelial inflammation. 13,14 Indeed, SIRT6 deficiency in EC resulted in an increased expression of pro-inflammatory cytokines, such as interleukin 1β, and increased transcriptional activity of NF-κB.…”