ReviewSestrin proteins in cardiovascular disease
Introduction
Sestrins are a highly conserved family of proteins which are induced by stress in cells [1]. Peeters H and Debeer P first defined and described sestrins in 2003 [2]. There are three sestrin isoforms: sestrin1, sestrin2 and sestrin3. Most vertebrates express all isoforms, while invertebrate species express only one [2]. Expression levels of sestrin are low in healthy human cells, but they are upregulated and exert different functions when cells suffer from injury, stress and other disorders or during the immune response [3]. Sestrins have three functional sites with the following activities: mechanistic target of rapamycin in complex (mTORC) regulation, reactive oxygen species (ROS) suppression and leucine binding [4]. Sestrins are expressed through activating several transcription factors including p53, forkhead box O (FoxO), CCAAT-enhancer-binding protein (c/EBP), activating transcription factor 4 (ATF4) and activator protein 1(AP-1) [3]. Many studies show that the sestrin-AMPK-mTORC pathway is a main regulatory pathway under those circumstances. Sestrins promote phosphorylation of threonine (Thr172) resulting in activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex-2 (TSC2). TSC2 negatively regulates mTORC signalling by converting Rheb-GTP into Rheb-GDP [5], whereas Parmigiani A and Peng M show that sestrins inhibit mTORC when AMPK is knocked out[6], [7]. They propose that sestrins can bind with GATOR2 and result in the release of GATOR1 from GATOR, leading to the dissociated GATOR1 depressing the activity of RagA/B and resulting in the inhibition of mTORC [7]. According to the research of MengLong Wang in 2018, sestrins exert different critical functions in the heart, lung, immune system, gastrointestinal tract, liver, nervous system and kidney [8] (see Fig. 1).
Section snippets
Sestrins in atherosclerosis
Numerous studies have demonstrated that lipid infiltration, response-to-injury hypothesis and immune response theory are the major pathologies of atherosclerosis (AS) [9], [10], [11]. Since sestrin proteins exert anti-inflammatory, anti-injury and protective effects during the progress of age-related diseases [1], many studies have been performed in animal models and human subjects in order to clarify the exact impact of sestrins in cardiovascular diseases. Hwan-Jin Hwang et al have confirmed
Sestrins in AMI, hypertension and arrhythmia
The inflammatory response plays a crucial role in AMI progress, where it is important in the repair of the myocardium but is also involved in myocardial remodelling and heart failure after myocardial infarction [22]. A previous study revealed that negative regulation of macrophage polarization to the M1 phenotype can reduce the immune response injury of vessels [23]. Yang KP showed that overexpression of sestrin2 suppressed the inflammatory response after AMI through its effect on M1
Sestrins in cardiac Hypertrophy, cardiac fibrosis and doxorubicin cardiotoxicity
Cardiac hypertrophy and cardiac fibrosis are complicated abnormalities that generally result in myocardial dysfunction over time. Cardiac fibroblasts proliferate, differentiate, and excrete ECM to maintain myocardial function under states of oxidative stress, high blood pressure, chronic ischaemia and more [36]. Some studies have shown that repression of sestrin1 enhances proliferation of cardiac fibroblasts [37], [38]. Gang sun reports that silencing of sestrin1 accelerates the proliferation
Conclusion
Existing studies have shown that sestrins play important protective roles in atherosclerosis, myocardial infarction, hypertension, atrial fibrillation, myocardial hypertrophy, and myocardial fibrosis. The main mechanisms of protection lie in its role in reducing immune injury, inhibiting fibroblast proliferation and reducing oxidative stress. More importantly, the expression levels of sestrin proteins in coronary artery diseases are positively correlated with the severity of the disease. We
Acknowledgement
YunFeng Sun and YaWei Wu contribute to this work equally.
All the authors declare no conflict of interest.
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