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. We have previously shown that statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, selectively induce the HO-1 isozyme in vivo following a large single oral dose. The objective in this study was to investigate the effects of chronic administration of statins on in vivo induction of HO-1 expression. Adult mice were given atorvastatin or rosuvastatin (5 mg/kg body weight) or vehicle (control) by daily intraperitoneal injections for 1, 2, or 3 weeks. At each time point, mice were sacrificed. HO activity and tissue carbon monoxide (CO) levels in the liver, lung, brain, and heart were measured and then expressed as fold change from control levels. Total serum bilirubin (TSB) and carboxyhemoglobin (COHb) levels were measured after 3 weeks of statin treatment. Heart HO activity significantly increased after 2 and 3 weeks of treatment with atorvastatin (1.24 ± 0.27 [n = 7, p = .04] and 1.27 ± 0.07 [n = 4, p = .0009], respectively) and rosuvastatin (1.20 ± 0.13 [n = 5, p = .02] and 1.48 ± 0.27 [n = 5, p = .01], respectively). After 3 weeks of treatment, similar increases in heart tissue CO and COHb levels with atorvastatin (1.30 ± 0.24 [n = 5, p = .023] and 1.92 ± 0.17 [n = 5, p = .001], respectively) and rosuvastatin (1.47 ± 0.13 [n = 3, p = .01] and 1.63 ± 0.12 [n = 5, p = .001], respectively) were also found. Significant increases in antioxidant capacity in the heart in both atorvastatin- (n = 4) and rosuvastatin- (n = 5) treaqted mice were also observed and were paralleled by elevations in TSB of 1.49 ± 0.15-fold (p = .001) and 1.14 ± 0.14-fold (p = .02) from baseline levels, respectively. We conclude that the induction of HO activity by chronic treatment with atorvastatin and rosuvastatin is primarily in the heart. Subsequent production of CO and bilirubin, bioactive metabolic products of HO-1, is the major mechanism by which statins exert their antioxidant actions on the cardiovascular system and confer cardiac cytoprotection.
This work was study was supported in part by National Institutes of Health grant #HD58013 and AstraZeneca grant #1RUSROSU0190.
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