Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease.
Proc Natl Acad Sci U S A
; 110(42): 17023-8, 2013 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-24082102
ABSTRACT
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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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
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Miócitos Cardíacos
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Apolipoproteínas D
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Miocárdio
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Antioxidantes
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2013
Tipo de documento:
Article