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|a Mani, D. R.
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|a Massachusetts Institute of Technology. Department of Biology
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|a Krieger, Monty
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|a Tsukamoto, Kosuke
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|a Zhang, Songwen
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|a Krieger, Monty
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|a Tsukamoto, Kosuke
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|a Zhang, Songwen
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|a Krieger, Monty
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|a Shi, Jianru
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|a Haagensen, Darrow E.
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|a Otsuka, Fumiyuki
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|a Guan, Jian
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|a Smith, Jonathan D.
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|a Weng, Wei
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|a Liao, Ronglih
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|a Kolodgie, Frank D.
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|a Virmani, Renu
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|a Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease
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|b National Academy of Sciences (U.S.),
|c 2014-04-07T17:28:08Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/86062
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|a 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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|a National Institutes of Health (U.S.) (Grant HL52212)
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|a National Institutes of Health (U.S.) (Grant HL066105)
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|a en_US
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|a Article
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|t Proceedings of the National Academy of Sciences
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