The roles of macrophage autophagy in atherosclerosis

Abstract

Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis.

Figure 1

Schematic illustration of the autophagy process in macrophages and recent advances in targeting autophagy for atherosclerotic treatments. Under conditions including nutrient insufficiency, hunger or increased ROS, cup-shaped phagophores with bilayer lipid membranes are formed that are composed of various types of Atgs. Spherical double-membrane autophagosomes subsequently form. On integration with lysosomes, autophagosomes turn into autolysosomes, which function in degradation. Two major signaling pathways regulate this process: an inductive pathway that involves Class-III PI3K-Beclin1 signaling and an inhibitory pathway that involves Class I PI3K-mTOR signaling. Several autophagy inducers are effective at positively intervening in autophagy. Of these, everolimus, resveratrol and berberine inhibit the autophagy suppressor mTOR, and berberine also activates AMPK. The overexpression of β-arrestin-1 and the activation of CB2R are thought to increase the expression of Beclin1 and LC3, contributing to the initiation of autophagy.

Figure 2

Schematic illustration of the roles of macrophage autophagy during the different steps of AS. During the initiation of AS, circulating monocytes move into the subendothelium of vessel walls, where they break through the endothelial cells and become macrophages. When macrophages ingest oxLDL or other forms of modified lipoproteins, they turn into foam cells. The accumulation of foam cells results in the formation of atherosclerotic plaques. Macrophage autophagy contributes to the inhibition of foam cell formation by reducing oxLDL ingestion by macrophages and increasing efferocytosis and cholesterol efflux in macrophages. It also inhibits the occurrence of plaque rupture and fall off by inhibiting apoptosis and inflammation in lesional plaques, which alleviates the severity of AS.