Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling

Abstract

Nitric oxide (NO) is an endogenously produced physiological signaling molecule that regulates blood flow and platelet activation. However, both the intracellular and intravascular diffusion of NO is severely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoproteins, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments, like blood and cardiomyocytes. We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe2+-NO, NO-ferroheme) either in solution within membranes or bound to albumin. Unexpectedly, we observed a rapid reaction of NO with free ferric heme (Fe3+) and a reduced thiol under physiological conditions to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when the hemin is solubilized in lipophilic environments, such as red blood cell membranes, or bound to serum albumin. NO-ferroheme albumin is stable, even in the presence of excess oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme-albumin administered intravenously to mice dose-dependently vasodilates at low- to mid-nanomolar concentrations. 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.

Use of an Antibacterial Mouthwash Alters the Gut Microbiome, Reduces Nutrient Absorption and Attenuates Diet-induced Obesity

“…As expected, in mice receiving regular diet (RD) chlorhexidine mouthwash signi cantly reduced plasma nitrite and RBC heme-NO (i.e., an NO signaling entity in the vasculature). 37,38 However, these effects were not observed in WD mice. Possibly, this could be explained by the lower nitrate content in the WD or that the high fat and sugar intake affected the ability of chlorhexidine to impact on the oral microbiome.…”