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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. ispartof: CARDIOVASCULAR RESEARCH vol:114 issue:4 pages:622-634 ispartof: location:England status: published

Dominant optic atrophy (DOA) is because of mutations in the mitochondrial protein OPA1. The disease principally affects retinal ganglion cells, whose axons degenerate leading to vision impairments, and sometimes other neuronal phenotypes. The exact mechanisms underlying DOA pathogenesis are not known. We previously demonstrated that the main role of OPA1, as a mitochondrial fusogenic and anti-apoptotic protein, are inhibited by interaction with the stress inducible pro-apoptotic BNIP3 protein. Because BNIP3 was recently reported to participate in autophagy and mitophagy, we tested the involvement of these processes in DOA pathogenesis. Using an in vitro neuronal model of DOA, we identified a BNIP3 down-regulation that reduced autophagy and mitophagy. Restoring BNIP3 had a biphasic effect, first rescuing autophagy and mitophagy levels but later leading to cell death. Similarly, in an in vivo mouse model of DOA, we showed that BNIP3 levels are decreased in young adult mice and increase to normal levels upon aging, paralleling disease progression. Altogether, our results indicate that the relationship between OPA1 and BNIP3 may have important bearings on DOA pathogenesis.