Key result
GIMAP6 deficiency drives inflammatory vasculopathy and accelerates early ASCVD independently of hyperlipidemia.
Why the study?
Atherosclerotic cardiovascular disease remains a major cause of mortality despite controlling hyperlipidemia, and the role of the immunoregulatory gene GIMAP6 in vascular integrity and atherosclerosis was unclear.
Does the loss or dysfunction of the GIMAP6 gene cause atherosclerotic vasculopathy and heart failure independently of systemic hyperlipidemia?
Does the loss or dysfunction of the GIMAP6 gene cause atherosclerotic vasculopathy and heart failure independently of systemic hyperlipidemia?
Identifies GIMAP6 as a critical immunoregulatory gene that protects against vascular inflammation and atherosclerosis independently of systemic hyperlipidemia.
Should not yet change practice; leaves open immune-mediated vasculopathy as a lipid-independent pathway for human cardiovascular disease.
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.
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Chen et al. (2026) studied Atherosclerotic cardiovascular disease (ASCVD). Loss or hypomorphic variants of GIMAP6 vs. Normal GIMAP6 function was evaluated on Atherosclerotic vasculopathy, cardiac ischemia, myocardial infarction, heart failure, and early ASCVD. Loss of the immunoregulatory gene GIMAP6 in mice and hypomorphic variants in humans cause inflammatory vasculopathy and accelerate early ASCVD independently of systemic hyperlipidemia.
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