Autophagy: an emerging therapeutic target in vascular diseases

Abstract

Autophagy is a cellular catabolic process responsible for the destruction of long-lived proteins and organelles via lysosome-dependent pathway. This process is of great importance in maintaining cellular homeostasis, and deregulated autophagy has been implicated in the pathogenesis of a wide range of diseases. A growing body of evidence suggests that autophagy can be activated in vascular disorders such as atherosclerosis. Autophagy occurs under basal conditions and mediates homeostatic functions in cells but in the setting of pathological states up-regulated autophagy can exert both protective and detrimental functions. Therefore, the precise role of autophagy and its relationship with the progression of the disease need to be clarified. This review highlights recent findings regarding autophagy activity in vascular cells and its potential contribution to vascular disorders with a focus on atherogenesis. Finally, whether the manipulation of autophagy represents a new therapeutic approach to treat or prevent vascular diseases is also discussed.

Figure 1

Overview of the autophagy machinery. Once activated, autophagy proceeds through four sequential steps, each step requiring specific regulatory proteins and complexes. Autophagy stimuli lead to the formation of two important complexes, Atg1/ULK1 and PI3K III/Beclin1, which are necessary for the initiation/nucleation step. During this step, phagophore structures are formed from plasma or organellar membranes, the double-lipid bilayer expands and wraps cytoplasmic materials yielding a closed multi-lamellar organelle termed autophagosome. Two ubiquitin-like conjugation systems are part of the elongation and maturation steps. One system involves the covalent conjugation of Atg12 to Atg5 with the help of the E1-like enzyme Atg7 and the E2-like enzyme Atg10. The Atg12–Atg5 conjugate in turn associates non-covalently with Atg16. The presence of Atg16 is required for the localization of Atg5 and Atg12 to the phagophore. The second system involves the conjugation of phosphatidylethanolamine to LC3/Atg8 by the sequential action of Atg4, Atg7 and Atg3. Lipid conjugation leads to the conversion of the soluble form of LC3-I to the autophagosome-associated form LC3-II. The autophagosome undergoes fusion with a late endosome or lysosome, to create an autolysosome, in which sequestered materials are degraded by lysosomal enzymes.