Protection against ischemia/reperfusion injury by high-density lipoprotein and its components.

A polipoprotein D is expressed in many tissues after injury , such as reperfusion injury after myocardial in-farction. Antioxidant activity of apolipoprotein D appears to confer cardioprotective properties after myocardial in-farction in a mouse model of severe rapidly progressing coronary atherosclerosis and in a mouse model of isch-emia/reperfusion injury. Mice with homozygous-null mutations in the high-density lipoprotein (HDL) scavenger receptor class B type I (SR-BI) and also with homozygous-null mutations in apolipoprotein E (apoE) experience development of severe occlusive coronary atherosclerosis and have myocardial infarction (MI) starting at approximately 31 days after birth. By 42 days after birth, ≈50% have died from cardiac causes. Tsukamoto et al 1 studied myocardial gene expression before MI (21 days after birth) and at 31 and 43 days after birth in these mice (SR-BI −/− /apoE −/−). The expression of the gene for osteopontin increased 416-fold, and the gene for apoD increased 80-fold. Because it had previously been reported that the gene for osteopontin increased post-MI, 2–5 the authors concentrated on the study of apoD. In an ischemia/reperfusion injury model, adenoviral expression of apoD in the liver was associated with high plasma apoD levels and reduced MI size. In contrast, deficiency of apoD (in apoD-null mice) was associated with increased MI size. The ability of apoD to protect cultured rat cardiomyocytes from hypoxia/reoxygenation injury correlated with the ability of apoD to inhibit oxidation in an in vitro antioxidant assay, suggesting that the antioxidant properties of apoD are important in mediating its cardioprotective properties. The authors determined the time course of disease development in the SR-BI −/− /apoE −/− mice and compared gene expression by microarray analysis at 21, 31, or 43 days of age. They then compared 89 genes whose relative transcript levels at 43 days were increased >6-fold in the hearts of the SR-BI −/− /apoE −/− mice to those induced in mouse hearts between 1 and 8 weeks after surgical coronary artery ligation as previously reported in the literature. Of the 89 genes induced >6-fold in the SR-BI −/− /apoE −/− mice at 43 days, 81 were shown to be induced after coronary ligation. The 81 genes included those encoding matricellular proteins , matrix proteases, tissue inhibitors of metalloproteinases, and inflammation-associated and fibrosis-associated proteins. In the coronary ligation experiment, apoD increased early (48 hours) after ligation and was substantially increased in nonin-farcted, but not in infarcted, tissue. Four days after the mice …