Thiol catalyzed NO-ferro-heme signaling

<p class="MsoNormal"><span class="normaltextrun"><span>Nitric oxide (NO) is an endogenously produced </span></span><span><span>signaling molecule that regulates blood flow and platelet activation. However, </span><span>intracellular and intravascular diffusion of NO </span></span><span>are s</span>everely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoprotein<span class="normaltextrun"><span>s, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments</span></span><span class="normaltextrun"><span><span><span>.</span></span></span><span> We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe</span></span><span class="normaltextrun"><span>^{<span><span>2+</span></span>}</span></span><span class="normaltextrun"><span><span>-NO</span>, NO-ferroheme. Unexpectedly, we observed a rapid reaction of NO with labile ferric heme (Fe</span></span><span class="normaltextrun"><span>^{<span><span>3+</span></span>}</span></span><span class="normaltextrun"><span><span>) and a reduced thiol to yield NO-ferroheme and a </span>thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when </span></span><span class="normaltextrun"><span><span>hemin is solubilized in lipophilic environments, such as red blood cell membranes or bound to serum album</span></span></span><span>in.</span> <span>The resulting </span><span>NO-fe</span><span class="normaltextrun"><span><span>rroheme</span> is stable, even in the presence of oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme albumin administered intravenously to mic</span></span>e <span>results in </span><span>d</span><span class="normaltextrun"><span><span>ose-dependent</span></span></span><span class="normaltextrun"><span><span> vasod</span></span></span><span>ilat</span><span>ion</span><span> at</span><span class="normaltextrun"><span><span><span> low- to mid-nanomolar concentrations. </span>In conclusion, we report the fastest rate of reductive nitrosylation observed to date to generate a NO-ferroheme molecule that resists oxidative inactivation, is soluble in cell membranes, and is transported intravascularly by albumin to promote potent vasodilation. </span></span><span class="eop"><span><span> </span></span></span></span></p>