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

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

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[superscript −/−]/apoE[superscript −/−] or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) an...

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Bibliographic Details
Main Authors: Mani, D. R., Tsukamoto, Kosuke, Zhang, Songwen, Krieger, Monty, Shi, Jianru, Haagensen, Darrow E., Otsuka, Fumiyuki, Guan, Jian, Smith, Jonathan D., Weng, Wei, Liao, Ronglih, Kolodgie, Frank D., Virmani, Renu
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: National Academy of Sciences (U.S.) 2014
Online Access:http://hdl.handle.net/1721.1/86062
https://orcid.org/0000-0003-4541-5181
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Summary: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[superscript −/−]/apoE[superscript −/−] 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[superscript +/−]/apoE[superscript −/−] 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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