Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease
| Autor: | Jonathan D. Smith, Songwen Zhang, Monty Krieger, Fumiyuki Otsuka, Frank D. Kolodgie, Ronglih Liao, Kosuke Tsukamoto, D. R. Mani, Wei Weng, Jianru Shi, Darrow E. Haagensen, Renu Virmani, Jian Guan |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Apolipoprotein E
Apolipoprotein D medicine.medical_specialty Microarray Myocardial Infarction Ischemia Myocardial Reperfusion Injury Coronary Artery Disease Lipocalin Antioxidants Coronary artery disease Mice Apolipoproteins E Internal medicine Animals Humans Medicine Myocytes Cardiac Myocardial infarction Rats Wistar Scavenger receptor Apolipoproteins D Cells Cultured Mice Knockout Multidisciplinary business.industry Myocardium Scavenger Receptors Class B medicine.disease Cell Hypoxia Disease Models Animal Endocrinology Female business |
| Zdroj: | Proceedings of the National Academy of Sciences |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 increasedsixfold 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|