Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis

Abstract

Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

Inflammatory Drivers of Cardiovascular Disease: Molecular Characterization of Senescent Coronary Vascular Smooth Muscle Cells

“…Cellular senescence has been proposed the key source of inflammation in atherosclerosis and cardiovascular disease (CVD) (Stojanović et al, 2020). Senescent cells are irreversibly cell cycle-arrested and characterized with a proinflammatory phenotype known as the senescence associated secretory phenotype (SASP) (Bennett and Clarke, 2016).…”

“…Senescence of various cell types has been implicated in CVD development (Stojanović et al, 2020). In particular, senescent vascular smooth muscle cells (VSMCs) were reported to be one of the key pro-inflammatory senescent cell populations, and were found in unstable, rupture-prone atherosclerotic plaques Uryga and Bennett, 2016;Hamczyk et al, 2018;Katsuumi et al, 2018).…”

“…Therapeutic options to target these senescent cells have recently emerged (Stojanović et al, 2020). However, the further development of these strategies and their adaptation for the cardiovascular system is limited by a lack of specific markers that would enable the detection of senescent cell populations.…”

“…Additionally, p16 and the senescence-associated β-galactosidase staining (SAβG) levels can be reversibly increased in macrophages (Hall et al, 2017). Most SASP factors can be secreted by immune cells (Stojanović et al, 2020). Moreover, specific markers to detect and differentiate senescent VSMCs from other cell populations are lacking.…”

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

“…The senolytic effect of 2DG potentially depends on the increased metabolic activity of senescent cells, which may have an impact on the progression of atherosclerosis [ 76 ]. Although some senolytics have been clinically approved or are already in clinical trials for oncologic diseases, idiopathic pulmonary fibrosis and chronic kidney disease [ 265 ], studies with senolytic drugs have only been performed in animal models of disease in the field of atherosclerosis, and clinical trials are currently awaited.…”