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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/86062 https://orcid.org/0000-0003-4541-5181 |
| _version_ | 1826201155864100864 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Mani, D. R. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:47:06Z |
| format | Article |
| id | mit-1721.1/86062 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:47:06Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/860622022-10-01T05:59:19Z Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease 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 Massachusetts Institute of Technology. Department of Biology Krieger, Monty Tsukamoto, Kosuke Zhang, Songwen Krieger, Monty 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. National Institutes of Health (U.S.) (Grant HL52212) National Institutes of Health (U.S.) (Grant HL066105) 2014-04-07T17:28:08Z 2014-04-07T17:28:08Z 2013-09 2013-07 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/86062 Tsukamoto, K., D. R. Mani, J. Shi, S. Zhang, D. E. Haagensen, F. Otsuka, J. Guan, et al. “Identification of Apolipoprotein D as a Cardioprotective Gene Using a Mouse Model of Lethal Atherosclerotic Coronary Artery Disease.” Proceedings of the National Academy of Sciences 110, no. 42 (October 15, 2013): 17023–17028. https://orcid.org/0000-0003-4541-5181 en_US http://dx.doi.org/10.1073/pnas.1315986110 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences |
| spellingShingle | 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 Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title | Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title_full | Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title_fullStr | Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title_full_unstemmed | Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title_short | Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| title_sort | identification of apolipoprotein d as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease |
| url | http://hdl.handle.net/1721.1/86062 https://orcid.org/0000-0003-4541-5181 |
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