Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo

https://doi.org/10.1016/j.bbrc.2006.03.036Get rights and content

Abstract

Heme oxygenase-1 (HO-1) plays a central role in antioxidant and anti-inflammatory actions, which may be mediated through its formation of biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors (statins) induce in vitro HO-1 expression and are reported to have pleiotropic benefits that reduce oxidative stress in the vasculature. We characterized the effects of statins on in vivo HO-1 expression in various extravascular tissues: liver, lung, brain, and heart. Adult mice were orally administered simvastatin, lovastatin, atorvastatin, or rosuvastatin. HO activity significantly increased in a statin- and tissue-specific manner, with all statins increasing heart and lung activity within 24 h. Significant elevations of HO-1 protein and mRNA were also observed in heart and lung after atorvastatin treatment. We conclude that in vivo HO-1 induction is statin- and tissue-specific. Through this pathway, statins may confer antioxidant and anti-inflammatory actions in the vasculature and extravascular systems.

Section snippets

Materials and methods

Animals. Adult (6–8 weeks old) FVB transgenic mice, with the transgene comprising of the 15-kb HO-1 promoter driving expression of the reporter gene luciferase (luc), or HO-1-luc [35], were obtained from the Stanford Transgenic Animal Facility (Stanford, CA) and provided water and food ad libitum.

Reagents. Statins: simvastatin, lovastatin (EMD Biosciences, La Jolla CA), atorvastatin (Pfizer, New York, NY), and rosuvastatin (AstraZeneca, Wilmington DE) were dissolved in 30-μl Tween 80. The

HO activity

Fig. 1 and Table 1 show HO activity in the liver, brain, lung, and heart tissues 24 h after treatment with statins. After treatment with simvastatin, HO activity significantly increased 1.12-, 1.19-, and 1.70-fold in the liver, lung, and heart, respectively. No significant change in brain HO activity was observed following simvastatin treatment. Atorvastatin and rosuvastatin treatment resulted in similar significant increases in HO activity in the brain (1.06- and 1.16-fold), lung (1.11- and

Discussion

Pleiotropic mechanisms beyond the reduction of plasma cholesterol have been repeatedly shown to contribute to the anti-atherogenic and tissue-protective properties of statins. Based on previously published protocols and dosing regimens of statins administered to mice [42], [43], we first characterized the effects of four statins with varying structures and lipophilicities on in vivo HO activity. All four statins tested induced HO activity, but had varying tissue specificity profiles (Table 1).

Acknowledgments

This work was supported in part by National Institutes of Health Grant #HD58013, the Mary L. Johnson Research Fund, and the Christopher Hess Research Fund.

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