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CARDIOVASCULAR

Nitric Oxide Inhibitor N-Nitro-L-arginine Methyl Ester Potentiates Induction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: A Novel Mechanism for Regulation of the Oxygenase

Departments of Urology (R.D.M.) and Biochemistry/Biophysics (X.W., M.D.M.), University of Rochester Medical Center, Rochester, New York

The biological significance of the heme oxygenase (HO) system's response to stress reflects functions of its products—CO and bile pigments. CO is a messenger molecule, whereas bile pigments are antioxidants and modulators of cell signaling. Presently, an unexpected mechanism for sustained suprainduction of renal HO-1 following ischemia/reperfusion injury is described. Inhibition of nitric-oxide synthase (NOS) activity by N-nitro-L-arginine methyl ester (L-NAME) at the resumption of reperfusion of rat kidney subjected to bilateral ischemia (30 min) was as effective as the most potent HO-1 inducer, the spin trap agent n-tert-butyl--phenyl nitrone (PBN), in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. Twenty-four hours after reperfusion, HO-1 mRNA measured 30-fold that of the control in the presence of L-NAME treatment; in its absence, the transcript increased to only 5-fold. At 4 h in the presence or absence of the L-NAME HO-1, mRNA was increased by 30-fold. The transcript was translated to active protein as indicated by Western blotting, immunohistochemistry, and activity analyses. L-NAME was not effective given 1 h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; ferritin expression in the kidney was not effected. It is reasoned that in tissue directly insulted by ischemia/reperfusion, increased production of NO radicals promotes the loss of HO-1 transcript. Because the absence of NO radicals and presence of PBN had a similar effect on HO-1, we propose that suprainduction of the gene is mainly caused by O₂ radicals formed on reperfusion. Inhibition of NOS is potentially useful for sustained induction of HO-1 in organs that will be subjected to oxidative-stress insult.

Address correspondence to: Dr. Mahin D. Maines, University of Rochester Medical Center, Department of Biochemistry/Biophysics, Box 712, 601 Elmwood Ave., Rochester, NY 14642. E-mail: mahin_maines{at}urmc.rochester.edu

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