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  • br Conclusion br Conflicts of interest br

    2019-07-06


    Conclusion
    Conflicts of interest
    Transparency document
    Acknowledgements This study was supported by grants from the Shanghai Municipal Health and Family Planning Commission Foundation (No. 2016ZB0306) and the National Natural Science Foundation of China (No. 81773719, No. 81703590).
    Introduction Atherosclerosis, with fatty streaks gradually developing into atheroma and characteristic plaques inside the arteries, is the main pathophysiological condition resulting in cardiovascular disease (CVD) [1, 2]. Despite of the emerging pharmacological interventions and lifestyle changes, atherosclerotic cardiovascular disease (ASCVD) remains to be a heavy health and economic burden globally [3, 4]. The pathologic mechanisms of atherosclerosis are complex, including elevated concentrations of lipoprotein cholesterol, chronic inflammatory responses, and arterial wall cell dysfunctions [5]. Among all the triggering factors for these mechanisms, ageing consistently presents the strongest association with atherosclerosis prevalence, and continues to be the major determinant of 10-year ASCVD risk [[6], [7], [8]]. One plausible explanation is that mechanisms related to ageing play vital roles in the pathophysiologic process of atherosclerosis. Among the various mechanisms, cellular senescence has been considered as a major contributor to tissue ageing [9]. In 1970s, Hayflick and Moorhead first defined “cellular senescence” as they discovered the limited capacity of dividing before entering a stable proliferative arrest in cultured normal human cells, also termed as “Hayflick limit” [[10], [11], [12]]. Cellular senescence is currently defined as the arrest during the cell cycle, which could be driven by either chronological ageing (endogenous sources) or multiple stimuli including oxidative stress, DNA damage and inflammation (exogenous sources) [13, 14]. In recent years, the association between cellular senescence and atherosclerosis has gained much attention, as more evidence has been brought that senescent CCK-8 chemicals (SNCs) exist in atherosclerotic plaques, and that SNCs could alter the pro-atherogenic events. Silent information regulator 2 (Sir2) proteins (sirtuins), is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase family [[15], [16], [17]]. Mounting researches have demonstrated the beneficial role of sirtuins in cardiovascular diseases via regulating cellular metabolism and a wide range of cellular functions [[18], [19], [20]]. The association between sirtuins and ageing begins with the finding that overexpression of sirtuins increased life span in yeast [21, 22]. Ever since, more studies have demonstrated the beneficial effects of sirtuins and senescence-related pathologies [23]. Over the past decades, the wide use of lipid-modifying drugs like statins has led to the reductions in atherosclerosis-associated cardiovascular events [24]. However, the risk of ASCVD is still high, fueling the development of new targets toward the treatment of atherosclerosis. This review aims to work toward an exploration of the link between cellular senescence and atherosclerotic progression, and to point a way forward toward the application of sirtuins-associated pharmaceutical controls over atherosclerosis.
    Cellular senescence in atherosclerosis
    Sirtuins: a chemotherapeutic target for atherosclerosis? Sirtuins (SIRT1-7) are a family of NAD+-dependent cellular deacetylases, acting as nutrient and metabolic sensors [[54], [55], [56]]. The critical role of sirtuins is potently involved in multiple metabolic processes including inflammation, gluconeogenesis, insulin sensitivity and renin-angiotensin-aldosterone system (RAAS) system [[57], [58], [59]]. The best evidence comes from the studies by M. Lagouge and J. A. Baur et al. that SIRT1 activation by resveratrol treatment improved metabolic profile in mouse model [60, 61]. Over the past 20 years, numerous studies have revealed the beneficial role of sirtuins in anti-ageing, as animal models with genetically sirtuins over-expression or treated with sirtuins activators or NAD+ precursors present improved organ function and longevity [62]. These evidences from yeast [21, 63, 64], worm [[65], [66], [67], [68]], fruit fly [[69], [70], [71]] and mouse [[72], [73], [74], [75]] have demonstrated that sirtuin knockout shortened longevity, while genetically-manipulated sirtuin over-expression or sirtuin activators extended longevity.