Statin treatment increases formation of carbon monoxide and bilirubin in mice: A novel mechanism of in vivo antioxidant protection

Heme oxygenase (HO) has a central role in cellular antioxidant defences and vascular protection, and it may mediate pleiotropic actions of drugs used in cardiovascular therapy. We investigated whether long-term use of statins upregulates HO activity and increases carbon monoxide (CO) and bilirubin levels in vivo. Adult FvB mice were given atorvastatin or rosuvastatin (5 mg/kg) daily by i.p. injections for 1, 2, or 3 weeks. HO activity, tissue CO, bilirubin, and antioxidant levels, total plasma bilirubin, and carboxyhemoglobin (COHb) were measured. Fold changes in heart HO activity significantly increased after 1, 2, and 3 weeks of atorvastatin (1.24 ± 0.06 (p ≤ 0.05); 1.29 ± 0.26 (p ≤ 0.03); 1.33 ± 0.08 (p < 0.01), respectively) and 2 and 3 weeks of rosuvastatin (1.23 ± 0.20 (p ≤ 0.03); 1.63 ± 0.42 (p < 0.01), respectively). Heart tissue CO and COHb levels also increased after 3 weeks with atorvastatin (1.30 ± 0.24 (p ≤ 0.05); 1.92 ± 0.17 (p ≤ 0.001), respectively) and rosuvastatin (1.47 ± 0.13 (p ≤ 0.004); 1.63 ± 0.12 (p ≤ 0.001), respectively). Significant increases in heart antioxidant levels were observed after statin treatment and corroborated by heart bilirubin content elevations. Antioxidant level increases were abolished by treatment with an HO inhibitor. These findings suggest that the induction of HO and the production of its products, CO and bilirubin, may be a mechanism by which statins exert antioxidant actions and confer cardioprotection in vivo.