Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease

Significance Coronary artery disease (CAD) is a major cause of death and disability. Genetically modified SR-BI/apoE double KO (dKO) mice spontaneously exhibit many features of human CAD, including hypercholesterolemia, clogged arteries, myocardial infarction (MI) (or heart attack), heart failure, and premature death. We identified many changes in gene expression in dKO hearts [e.g., increases in apolipoprotein D (apoD)] during CAD development and compared them to those occurring after surgically induced MI. Additional studies showed that apoD partially protected mice from experimentally induced MI (temporarily blocking a coronary artery) and partially protected isolated rat heart muscle cells from temporary oxygen deprivation. We conclude that dKO mice are useful models for human CAD and apoD may naturally help protect hearts from clogged arteries. Mice with homozygous null mutations in the HDL receptor (scavenger receptor class B, type I, or SR-BI) and apolipoprotein E (apoE) genes [SR-BI/apoE double KO (SR-BI−/−/apoE−/− or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 d of age). Using microarray mRNA expression profiling, we identified genes whose expression in the hearts of dKO mice changed substantially during disease progression [at 21 d of age (no CAD), 31 d of age (small myocardial infarctions), and 43 d of age (extensive myocardial infarctions) vs. CAD-free SR-BI+/−/apoE−/− controls]. Expression of most genes that increased >sixfold in dKO hearts at 43 d also increased after coronary artery ligation. We examined the influence and potential mechanism of action of apolipoprotein D (apoD) whose expression in dKO hearts increased 80-fold by 43 d. Analysis of ischemia/reperfusion-induced myocardial infarction in both apoD KO mice and wild-type mice with abnormally high plasma levels of apoD (adenovirus-mediated hepatic overexpression) established that apoD reduces myocardial infarction. There was a correlation of apoD’s ability to protect primary cultured rat cardiomyocytes from hypoxia/reoxygenation injury with its potent ability to inhibit oxidation in a standard antioxidation assay in vitro. We conclude that dKO mice represent a useful mouse model of CAD and apoD may be part of an intrinsic cardioprotective system, possibly as a consequence of its antioxidation activity.

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