Macrophage PHACTR1 in efferocytosis and atherosclerosis

Defective clearance of apoptotic cells (defective efferocytosis) has been implicated in human diseases that are driven by chronic inflammation and delayed resolution. In particular, there is clear evidence for defective efferocytosis by macrophages in clinically dangerous human atherosclerotic plaques. However, the mechanisms of defective efferocytosis in advanced atherosclerosis are unknown. Hence, our lab has been working to elucidate the mechanisms of impaired efferocytosis during atheroprogression, including determining if genetic polymorphisms associated with coronary artery disease (CAD) risk may function, at least in part, by causing defective efferocytosis. In this context, I have become interested in a high-frequency CAD-risk variant rs9349379 which is found in the third intron of the Phosphatase and actin regulator 1(PHACTR1) gene. PHACTR1 is an actin-binding protein that functions as a modulator of protein phosphatase 1(PP1) and actin remodeling. I have pilot data showing that rs9349379 variant is associated with lower levels of PHACTR1 and decreased efferocytosis in human macrophages. Further, efferocytosis is impaired by partial silencing of PHACTR1 in human macrophages. . However, the mechanisms of PHACTR1 induced efferocytosis and the role of the PHACTR1 variant in CAD are unknown. The overarching objective of this proposal is to investigate hypotheses that PHACTR1 enables efferocytosis through its role in actin signaling and that the higher CAD risk in subjects carrying rs9349379 variant may function in part by impairing lesional macrophage efferocytosis. Toward this goal, I will first explore the mechanism by which PHACTR1 mediate efferocytosis in macrophages and the link between human CAD risk PHACTR1 variant and defective efferocytosis. I will then test the central hypothesis that hematopoietic PHACTR1 deficiency results in impaired lesional efferocytosis and plaque necrosis. Through these studies and the power of human genetics, I hope to provide the basis for a valuable new target for atherosclerotic CAD. (AHA Program: Postdoctoral Fellowship)