Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis

Abstract

In the present review, we describe the causes and consequences of loss of vascular smooth muscle cells (VSMCs) or their function in advanced atherosclerotic plaques and discuss possible mechanisms such as cell death or senescence, and induction of autophagy to promote cell survival. We also highlight the potential use of pharmacological modulators of these processes to limit plaque progression and/or improve plaque stability. VSMCs play a pivotal role in atherogenesis. Loss of VSMCs via initiation of cell death leads to fibrous cap thinning and promotes necrotic core formation and calcification. VSMC apoptosis is induced by pro-inflammatory cytokines, oxidized low density lipoprotein, high levels of nitric oxide and mechanical injury. Apoptotic VSMCs are characterized by a thickened basal lamina surrounding the cytoplasmic remnants of the VSMC. Inefficient clearance of apoptotic VSMCs results in secondary necrosis and subsequent inflammation. A critical determinant in the VSMC stress response and phenotypic switching is autophagy, which is activated by various stimuli, including reactive oxygen and lipid species, cytokines, growth factors and metabolic stress. Successful autophagy stimulates VSMC survival, whereas reduced autophagy promotes age-related changes in the vasculature. Recently, an interesting link between autophagy and VSMC senescence has been uncovered. Defective VSMC autophagy accelerates not only the development of stress-induced premature senescence but also atherogenesis, albeit without worsening plaque stability. VSMC senescence in atherosclerosis is likely a result of replicative senescence and/or stress-induced premature senescence in response to DNA damaging and/or oxidative stress-inducing stimuli. The finding that VSMC senescence can promote atherosclerosis further illustrates that normal, adequate VSMC function is crucial in protecting the vessel wall against atherosclerosis.

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…In addition, the production of metalloproteinases from senescent cells can further weaken the fibrous cap. Therefore, major mechanisms of plaque stabilization are impaired, and additional antigens might be uncovered that further amplify the inflammatory response 154 . Preclinical studies have shown that activated subtypes of T and B lymphocytes in plaques contribute to plaque instability, leading to an increase in the risk of cardiovascular disease 155 .…”

Macrophage-Based Therapies for Atherosclerosis Management

“…After activation of M1 macrophages, expression of inducible nitric oxide synthase (iNOS), CD86, and major histocompatibility complex II (MHC II) was upregulated, and multiple proinflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-12 (IL-12), and proinflammatory medium NO were secreted [4,62]. These proinflammatory factors can lead to endothelial injury, promote oxidative stress, enhance apoptosis, and accelerate the calcification rate of necrotic nucleus [63].…”

SIRT1 and Gender Differences in Atherosclerotic Cardiovascular Disease

“…Activation of SIRT1, a homolog of the yeast lifespan regulator Sir2, was reported to prolong the lifespan of rodents, whereas overexpression of SIRT1 in vascular smooth muscle (VSMC) or vascular endothelial cells was reported to suppress senescence and extend the survival of these cells 6) . It has been suggested that SIRT1 is protective for vascular senescence through the activation of endothelial nitric oxide synthase (eNOS), inhibition of reactive oxygen species (ROS), inflammation, and DNA damage 7) . Donato et al indicated that reductions in SIRT-1 and eNOS activities play essential roles in vascular endothelial dysfunction with aging in both mice and human 8) .…”