38 STATINS AS TISSUE-SPECIFIC INDUCERS OF IN VIVO HEME OXYGENASE EXPRESSION

Heme oxygenase (HO) is the rate-limiting enzyme in degrading heme to form bilirubin, and thus serves as an ideal therapeutic target for preventing neonatal jaundice. Understanding the regulatory pathways of HO is crucial for developing strategies for this disorder. Statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, have been reported to induce HO-1. Our objective was to characterize the effects of statins with different structures and lipophilicities on in vivo induction of HO-1 expression. Adult FVB mice (6-8 weeks old) were orally administered 100 mg/kg body weight of simvastatin, lovastatin, atorvastatin, or rosuvastatin. 24 hours after treatment, mice were sacrificed, and tissues were harvested, sonicated, and then analyzed for HO activity [carbon monoxide (CO) formation] by gas chromatography and HO proteins by Western blot. HO activity was calculated as pmol CO produced/hour/mg fresh weight. HO protein levels were measured by densitometry. All values were then expressed as mean ± SD percent of control levels (*p ≤ .03) as follows: Simvastatin did not affect brain HO activity. Liver HO activity was not induced by atorvastatin or rosuvastatin. Lovastatin increased HO activity in all tissues. Interestingly, all statins significantly increased HO activity in the heart and lung. When HO protein levels were measured in atorvastatin-treated mice, corresponding significant increases in HO-1 protein in the heart (132 ± 39%; n = 6) and lung (136 ± 13%; n = 4) were found, whereas no changes in HO-2 protein levels were observed in either tissue. We conclude that the induction of HO activity is statin- as well as tissue-specific. However, further studies are needed to elucidate the exact mechanism by which statins differentially induce HO expression in various organs.This work was study was supported in part by National Institutes of Health grant #HD58013.