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. 2013 Oct 15;110(42):17023-8. doi: 10.1073/pnas.1315986110. Epub 2013 Sep 30.

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.

Keywords: antioxidant; lipocalin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Apolipoproteins D / blood*
  • Apolipoproteins D / genetics
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Cell Hypoxia / genetics
  • Cells, Cultured
  • Coronary Artery Disease / blood*
  • Coronary Artery Disease / genetics
  • Coronary Artery Disease / metabolism
  • Coronary Artery Disease / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Mice
  • Mice, Knockout
  • Myocardial Infarction / blood
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / blood
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Rats, Wistar
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism

Substances

  • Antioxidants
  • Apolipoproteins D
  • Apolipoproteins E
  • Scarb1 protein, mouse
  • Scarb1 protein, rat
  • Scavenger Receptors, Class B

Associated data

  • GEO/GSE49937