Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure

Area of Science:

• Immunology
• Cardiovascular Biology
• Genetics

Background:

• Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of mortality despite efforts to control hyperlipidemia.
• The precise genetic and immunologic factors contributing to ASCVD independent of lipid levels are not fully understood.

Purpose of the Study:

• To investigate the role of the GTPase of immunity-associated protein 6 (GIMAP6) gene in the development of cardiovascular disease.
• To determine if GIMAP6 deficiency contributes to atherosclerosis in the absence of hyperlipidemia.

Main Methods:

• Utilized a mouse model with a genetic deficiency in GIMAP6.
• Assessed the development of vasculopathy, atherosclerosis, and cardiac pathology.
• Examined human genetic data for associations between GIMAP6 variants and cardiovascular disease.

Main Results:

• GIMAP6 deficiency led to inflammatory vasculopathy and accelerated atherosclerosis, independent of hyperlipidemia.
• Pathologic changes resulted in cardiac ischemia, myocardial infarction, heart failure, and premature death.
• Rare deleterious GIMAP6 variants in humans were associated with premature severe cardiovascular disease.

Conclusions:

• GIMAP6 plays a critical protective role against the development of atherosclerotic cardiovascular disease.
• GIMAP6 deficiency can drive cardiovascular pathology through inflammatory mechanisms.
• GIMAP6 represents a novel therapeutic target for preventing and managing cardiovascular disease.