Cellular Senescence in Cardiovascular Diseases: A Systematic Review

Abstract

Aging is a prominent risk factor for cardiovascular diseases, which is the leading cause of death around the world. Recently, cellular senescence has received potential attention as a promising target in preventing cardiovascular diseases, including acute myocardial infarction, atherosclerosis, cardiac aging, pressure overload-induced hypertrophy, heart regeneration, hypertension, and abdominal aortic aneurysm. Here, we discuss the mechanisms underlying cellular senescence and describe the involvement of senescent cardiovascular cells (including cardiomyocytes, endothelial cells, vascular smooth muscle cells, fibroblasts/myofibroblasts and T cells) in age-related cardiovascular diseases. Then, we highlight the targets (SIRT1 and mTOR) that regulating cellular senescence in cardiovascular disorders. Furthermore, we review the evidence that senescent cells can exert both beneficial and detrimental implications in cardiovascular diseases on a context-dependent manner. Finally, we summarize the emerging pro-senescent or anti-senescent interventions and discuss their therapeutic potential in preventing cardiovascular diseases.

Keywords: Cardiac aging; Cardiomyocytes; Cardiovascular diseases; Cellular senescence; Senotherapy.

Figure 1.

The mechanism in promoting cellular senescence in cardiovascular diseases. Telomere shortening, DNA damage, telomere damage, mitochondrial dysfunction and oxidative stresses can result in telomere length-dependent (replicative senescence) and length-independent (stress-induced premature senescence, SIPS) senescence in cardiovascular diseases.

Figure 2.

The hallmarks of senescent cells. (1) Irreversible cell cycle arrest. (2) Senescent cells display a characteristic enlarged and flatten morphological changes. (3) Increased senescence-associated β-galactosidase (SA-β-gal) activity. (4) Permanent cell-cycle withdrawal requires the expression of cyclin-dependent kinase inhibitors (CDKIs), most notably the P21 and p16. (5) Activation of the senescence-associated secretory phenotype (SASP), a bioactive secretome containing cytokines, chemokines, growth factors, proteases and other signaling molecules. (6) DNA damage response (DDR) (including DNA damage in telomere regions).

Figure 3.

The pathways in regulating cell cycle arrest. The multiple stresses activate DNA damage response (DDR), which directly activates p53 and its downstream target p21 via the kinase cascades involving apical kinases ataxia telangiectasia mutated (ATM), ATR and the downstream kinases CHK2 and CHK1. P21 can inhibit the activation of CDK2. P16 can increase during stressful insult and inhibit CDK4/6. Together, the CDKIs (p16 and p53/p21) inhibit CDK2/4/6 and then suppress the phosphorylation of retinoblastoma protein (Rb). The nonphophorylated Rb inhibit the transcriptional activity of E2F and result in cell cycle arrest.

Figure 4.

The pathological processes of cellular senescence in cardiovascular diseases. The senescent cardiovascular cells exert both beneficial and detrimental effect in cardiovascular diseases in a context-dependent manner. On the on hand, the senescent cells can restrict the fibrosis and prevent cardiac remodeling during ageing-related cardiovascular diseases. Moreover, senescence-associated secretory phenotypes (SASP) can modulate inflammation and promote angiogenesis during cardiac regeneration and myocardial infarction by bystander effects, which contributing to decreased cardiac dysfunction. On the other hand, the senescence is proposed as a key negative mechanism in promoting various age-related cardiovascular diseases (including atherosclerosis, heart rupture post AMI, cardiac aging, abdominal aortic aneurysm (AAA) and hypertension).