Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure.

Controlling hyperlipidemia has reduced but not eliminated atherosclerotic cardiovascular disease (ASCVD) as a major cause of human mortality. Here, we report that loss of the immunoregulatory gene GTPase of immunity-associated protein 6 (Gimap6) in mice causes an inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia. These vascular abnormalities cause progressive cardiac ischemia, myocardial infarction, and heart failure, culminating in early death. GIMAP6 loss precipitates early endothelial barrier failure and a mitochondrial reactive oxygen species (ROS)-PPARγ-CD36 lipid-influx cascade that lowers the threshold for foam-cell formation and induces IL-6/MCP-1/TNF-mediated inflammation. Human hypomorphic GIMAP6 variants, including the African-ancestry-enriched V65I allele, are associated with altered monocyte redox balance, increased CD36-mediated lipid uptake, and early ASCVD. Thus, GIMAP6 is a crucial safeguard for vascular integrity that restrains endothelial dysfunction, macrophage foam cell generation, and inflammation that can cause lethal ASCVD independently of systemic hyperlipidemia.