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

Abstract

Heme oxygenase-1 knockout, H mox

Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice

“…All of the female HO-1 Ϫ/Ϫ mice used in this study were bred in University of Missouri facilities and were used at 8 -12 wk of age. Genotyping was done on lysates from tail samples according to previously used methods (20). Experimental procedures were performed in compliance with institutional guidelines for humane animal care and use and were approved by the Institutional Animal Care and Use Committee.…”

“…Moreover, HO-1 Ϫ/Ϫ mice have been reported to develop nitrate tolerance, which was associated with reduced levels of soluble guanylate cyclase (sGC) (20). HO-1 is an inducible enzyme that conveys cytoprotection by producing biliverdin along with the products iron and carbon monoxide (45).…”

“…Indeed, a number of preconditioning strategies have been associated with increased levels of HO-1 protein during delayed or late-phase preconditioning (21,48). We proposed that an important component of that protection was related to HO-1 maintaining the heme iron of sGC in a reduced state (Fe 2ϩ ) that would retain sensitivity to nitric oxide (NO) (20). In that study, we made use of two drugs: one that was a stimulator (BAY 41-2272) of reduced sGC and one that was a more effective activator (BAY 60-2770) of oxidized (heme-free) sGC (10,24).…”

“…In that study, we made use of two drugs: one that was a stimulator (BAY 41-2272) of reduced sGC and one that was a more effective activator (BAY 60-2770) of oxidized (heme-free) sGC (10,24). Superior mesenteric arteries (SMAs) from HO-1 Ϫ/Ϫ mice were more responsive to the sGC activator than those from WT mice (20). This indicated that HO-1 Ϫ/Ϫ had more of sGC in an oxidized heme-free state, which would not be responsive to NO.…”

“…It was our objective to determine whether preconditioning with BAY compounds 10 min (early phase) or 24 h (late phase) before I/R would convey protection from inflammation and retain responses to ACh in mesenteric vessels. We also evaluated the effectiveness of these compounds in HO-1 Ϫ/Ϫ mice that were susceptible to ROS damage, where sGC levels are reduced and nitrate tolerance develops with an associated reduction in responses to ACh (20).…”