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

Abstract

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 ϳ30-fold that of the control in the presence of L-NAME treatment; in its absence, the transcript increased to only ϳ5-fold. At 4 h in the presence or absence of the L-NAME HO-1, mRNA was increased by ϳ30-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 O 2 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.Until recently, cellular degradation of the heme molecule (Fe-protoporphyrin IX, hemin) by the heme oxygenase (HO) system was viewed primarily in context of a mechanism for dispensing senescent heme compounds and recycling of iron. Other products formed in the course of catalytic activity of the HO system-CO and bile pigments-were solely considered in context of their toxicity. The view regarding the HO system dramatically changed when heme degradation products were identified as vital regulating factors in the cell. Compelling evidence has been presented showing that CO, in analogy with NO, is a signal molecule for the generation of cGMP and plays a role in neuronal signaling, vascular tone relaxation, as well as anti-apoptotic and apoptotic gene expression (Morita et al

In vivo effects of hemin and nitric oxide donors on parameters of heme metabolism in rat liver and serum

“…Peroxynitrite that is one of NO metabolites is the inhibitor of HO activity through the nitration of tyrosine residues in HO-1 and cysteine residues in HO-2 (Kinobe et al, 2004). The inhibitory effect of NO on heme oxygenase was also shown under action of NOS inhibitors (Mayer et al, 2003). In our experiments NO donors affected neither the basal level of HO activity nor the induction of HO by hemin (Table 4).…”

New Insights into Biliverdin Reductase Functions: Linking Heme Metabolism to Cell Signaling

“…Protein phosphorylation and dephosphorylation are essential components of signal transduction in the cell in response to various intra-and extracellular stimuli: hormones, metal complexes, and others. elements (1,41), and Maf proteins heterodimerize with the AP-1 family of transcription factors (6), formation of a complex between BVR and Maf would block the repressor Bach-1 activity and allow induction of ho-1 expression, consistent with that seen in ischemia/reperfusion injury (37).…”

Beneficial Effects of Heme Oxygenase-1 Up-Regulation in the Development of Experimental Inflammation Induced by Zymosan

“…Although the involvement of HO-1 in mediating protective effects has focused primarily on cardiovascular diseases (Yet et al, 1999;Melo et al, 2002;Mayer et al, 2003), it is becoming apparent that this enzyme plays a broader role in …”