IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway

Abstract

Acute coronary syndrome (ACS) caused by plaque rupture (PR) is the chief culprit behind cardiovascular death, yet its exact mechanism remains unclear. Immunity-related GTPase (IRGM/Irgm1) has been widely studied in several inflammatory diseases, but the role of IRGM/Irgm1 in atherosclerosis is poorly characterized. Here, we shed light on the mechanism by which IRGM/Irgm1 contributes to plaque vulnerability in atherosclerosis. We first identified ruptured and non-ruptured plaques by optical coherence tomography, and strikingly found that serum IRGM was highly expressed in ST-segment elevation myocardial infarction patients with PR. Next, we used ApoE-/-Irgm1+/+ and ApoE-/-Irgm1+/- mice and corresponding bone marrow chimeras to establish a model for advanced atherosclerosis, and found that Irgm1 could aggravate progression of atherosclerotic plaques. We confirmed that Irgm1 contributes to macrophage apoptosis by promoting the production of reactive oxygen species. Finally, we discovered that Irgm1 induces macrophage apoptosis by activating the MAPK signaling pathway. Our findings highlight the mechanism by which IRGM/Irgm1 contributes to the formation of vulnerable plaques and may offer a novel target for the timely treatment of ACS.