Chaperone-mediated autophagy protects against atherosclerosis

Abstract

Atherosclerosis, the leading cause of cardiovascular death, is driven by hyperlipidemia, inflammation and aggravated by aging. As chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, diminishes with age and is inhibited by lipid excess, we studied if the decline in CMA could contribute to atherosclerosis pathogenesis. We found that CMA declines in human and murine vasculature with disease progression. Inhibition and reactivation of CMA using transgenic mouse models establishes a protective effect of CMA against atherogenesis. CMA upregulation ameliorates both systemic metabolic parameters, and vascular cell function. Our work suggests CMA reactivation could be a viable therapeutic strategy to prevent and reduce cardiovascular disease.

Keywords: Cardiovascular disease; cholesterol; inflammation; insulin; lysosomes; macrophages; smooth muscle cells.

Figure 1.

Protective role of CMA against atherosclerosis. Top: Active CMA in vascular cells is protective against lipotoxicity and prevents the dedifferentiation of vascular smooth muscle cells and the pro-inflammatory phenotype of macrophages associated with atherosclerosis. Bottom: Blockage of CMA in vivo increases vulnerability to pro-atherosclerotic challenges by accentuating systemic metabolic changes and worsening atherosclerotic plaque phenotype. Reverting the decrease in CMA activity observed during chronic exposure to pro-atherosclerotic challenges is effective in reducing vascular disease severity and slowing down disease progression.