Induction of Heme Oxygenase-1 During Endotoxemia Is Downregulated by Transforming Growth Factor-ß1

From the Cardiovascular Biology Laboratory, Harvard School of Public Health (A.P., P.W., L.C.F., G.S.H., S.-F.Y., M.A.P.), the Department of Medicine, Harvard Medical School (A.S., G.S.H., M.A.P.), the Cardiac Unit, Massachusetts General Hospital (G.S.H.), and the Pulmonary and Critical Care Division, Brigham and Women's Hospital (A.S., M.A.P.), Boston, Mass.

Correspondence to Mark A. Perrella, MD, Cardiovascular Biology Laboratory, Building 2, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115. E-mail perrella{at}cvlab.harvard.edu

Abstract—Heme oxygenase (HO)-1 generates CO, a gas with vasodilatory properties, during heme metabolism. HO-1 is expressed highly in vascular tissue after endotoxin stimulation, and generation of CO through the HO-1 pathway contributes to the hemodynamic compromise of endotoxic shock. Shock related to endotoxemia is an immune-mediated process that involves the generation of proinflammatory cytokines such as interleukin (IL)-1ß. Because transforming growth factor (TGF)-ß1 is a modulator of immune-mediated inflammatory responses and it blocks the hypotension of endotoxic shock, we determined whether TGF-ß1 could be used to reduce expression of HO-1 in vascular tissue and smooth muscle cells. In a rat model of endotoxic shock, lipopolysaccharide-induced HO-1 mRNA and protein expression was reduced by TGF-ß1 in highly vascularized tissue, such as heart and lung, by Northern and Western analysis. Furthermore, TGF-ß1 downregulated HO-1 mRNA after its induction by IL-1ß in vascular smooth muscle cells in culture. TGF-ß1 also decreased HO-1 but not HO-2 protein expression in these cells. TGF-ß1 decreased HO enzyme activity induced in IL-1ß–treated vascular smooth muscle cells to a level not different from that in vehicle-treated cells. These studies suggest that this downregulation of HO-1 mRNA and protein expression and decrease in IL-1ß–induced HO enzyme activity may contribute to the beneficial effect of TGF-ß1 on endotoxic shock.

Key Words: vascular smooth muscle cell • endotoxic shock • gene expression • enzyme activity

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