Simvastatin attenuates TNF-α-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

Abstract

Abstract. Endothelial progenitor cells (EPCs) originate from the bone marrow and can be classified as either early or late EPCs. The focus of this study was on late EPCs, as they play an important role in angiogenesis and vascular proliferation. Evidence suggests that inflammatory and oxidative changes can increase EPC apoptosis. Of note, tumor necrosis factor-α (TNF-α) is a contributing risk factor to the development of atherosclerosis and plays a key role as both an inflammatory mediator and an inducer of apoptosis in endothelial cells. Additionally, a member of the sirtuin family, silent information regulator type-1 (SIRT1), promotes cell survival by repressing p53-and non-p53-dependent apoptosis in response to DNA damage and oxidative stress. Statins have also been shown to play a key role in the prevention of endothelial apoptosis and senescence via their lipid-lowering and anti-inflammatory actions. However, there is little evidence that statins themselves attenuate EPC apoptosis induced by TNF-α. The aim of this study was to demonstrate the effectiveness of one of the most commonly used statins, simvastatin, on decreasing TNF-α-induced apoptosis in EPCs. The results indicated that SIRT1 protein expression was decreased by TNF-α in a time-and dose-dependent manner and that while TNF-α caused a marked increase in the percentage of apoptotic EPCs, application of simvastatin decreased this percentage. A high concentration of simvastatin promoted the expression of SIRT1 and increased the proliferation of EPCs. In conclusion, findings of this study showed that simvastatin is crucial in counteracting the TNF-α-induced apoptosis of EPCs and that this protection may involve the actions of SIRT1.

Role of NADPH Oxidase-4 in Human Endothelial Progenitor Cells

“…Indeed, many lines of evidence indicate that NOX2-derived oxidative stress reduces circulating EPCs in diabetic patients as well as hampering the neovascularization efficiency of EPCs in an experimental model of hind limb ischaemia in aged mice (Turgeon et al, 2012). Moreover, separate studies show that the pro-inflammatory cytokine TNFα also activates NOX2 and reduces the viability of endothelial cells (Frey et al, 2002; Li et al, 2005; Schroder et al, 2012) and EPCs (Du et al, 2014). Consistent with these studies, we found chronic exposure to TNFα induces NOX2 expression and decreases survival of EPCs.…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…In regards to apoptotic pathways, SIRT1 activation can block external membrane PS exposure during the early phases of apoptosis in mature cells (70, 149–151). SIRT1 also can counteract apoptosis initiated by tumor necrosis factor-α (TNF-α) in endothelial progenitor cells (152). Loss of SIRT1 expression in endothelial progenitor cells leads to apoptotic cell death that can occur in smokers and chronic obstructive disease patients (153).…”

“…SIRT1 pathways are involved in vascular survival and senescence (88, 152, 161), atherosclerosis (162–166), lifespan extension (4, 167–169), diabetic retinopathy (170), cellular metabolism and DM (14, 17, 20, 115, 145, 171, 172), oxidative stress pathways (58, 148, 173–179), and neuronal survival and cognition (11, 113, 180–183). …”

Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease

“…However, insufficient SIRT1 activity may have a detrimental affect upon vascular cell survival (23, 78, 79) and block protection against cardiovascular disease (53, 80–82). Overall, SIRT1 controls multiple cellular functions that are involved with modulation of vascular survival and senescence (18, 83, 84), control of vascular tone through the transient receptor potential cation channel A1 (TRPA1) (85), development of atherosclerosis (80, 86–89), extension of lifespan (42, 73, 90, 91), alterations in cellular metabolism (10, 31, 57, 92–96), enhancement of neuronal survival and cognition (46, 59, 92, 97), and protection against oxidative stress (58, 81, 94, 98–103). …”