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Heme Oxygenase-1 Deficiency Leads to Alteration of Soluble Guanylate Cyclase Redox Regulation

2010; American Society for Pharmacology and Experimental Therapeutics; Volume: 335; Issue: 1 Linguagem: Inglês

10.1124/jpet.110.169755

1521-0103

Allan Jones, William Durante, Ronald J. Korthuis,

Thermal Regulation in Medicine

Heme oxygenase-1 knockout, H mox 1(−/−), mice exhibit exacerbated vascular lesions after ischemia-reperfusion and mechanical injury. Surprisingly, we found no studies that reported contractile responses and sensitivity to vasorelaxants in H mox 1(−/−) mice. The contractile responses [superior mesenteric arteries (SMA), from female H mox 1(−/−) mice] exhibited increased sensitivity to phenylephrine ( p < 0.001). Cumulative addition of acetylcholine relaxed SMA, with the residual contraction remaining 2 times higher in H mox 1(−/−) mice ( p < 0.001). Sodium nitroprusside (SNP, an NO donor) and 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole [YC-1; acts directly on soluble guanylate cyclase (sGC)] led to further relaxation, yet the residual contraction remained 2 to 3 times higher in H mox 1(−/−) than H mox 1(+/+) mice ( p < 0.001). Branches from H mox 1(−/−) mesenteric and renal arteries also showed reduced relaxation ( p < 0.025). Relaxation of SMA was measured to 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4′-(trifluoromethyl) biphenyl-4-yl] methoxy}phenyl)ethyl]amino}benzoic acid (BAY 60-2770), which is a more effective activator of oxidized/heme-free sGC; and to 5-cyclopropyl-2-{1-(2-fluoro-benzyl)-1 H -pyrazolo[3,4- b ]pyridin-3-yl}-pyrimidin-4-ylamine (BAY 41-2272), a more effective stimulator of reduced sGC. H mox 1(−/−) arteries were 15 times more sensitive to BAY 60-2770 ( p < 0.025) than were H mox 1(+/+) arteries. Pretreatment with 1 H -[1,2,4]oxadiazolo[3,4- a ]quinoxalin-1-one (ODQ), an oxidizer of sGC, predictably shifted the BAY 60-2770 response of H mox 1(+/+) to the left ( p < 0.01) and BAY 41-2272 response to the right ( p < 0.01). ODQ had little effect on the responses of H mox 1(−/−) arteries, indicating that much of sGC was oxidized/heme-free. Western analyses of sGC in SMA indicated that both α1and β1 subunit levels were reduced to <50% of H mox 1(+/+) level ( p < 0.025). These findings support the hypothesis that the antioxidant function of H mox 1 plays a significant role in the maintenance of sGC in a reduced state, which is resistant to degradation and is sensitive to NO. This function may be especially important in reducing vascular damage during ischemia-reperfusion injury.