Nitrite Signaling in Pulmonary Hypertension: Mechanisms of Bioactivation, Signaling, and Therapeutics

Abstract

Significance: Pulmonary arterial hypertension (PAH) is a disorder characterized by increased pulmonary vascular resistance and mean pulmonary artery pressure leading to impaired function of the right ventricle, reduced cardiac output, and death. An imbalance between vasoconstrictors and vasodilators plays an important role in the pathobiology of PAH. Recent Advances: Nitric oxide (NO) is a potent vasodilator in the lung, whose bioavailability and signaling pathway are impaired in PAH. It is now appreciated that the oxidative product of NO metabolism, the inorganic anion nitrite (NO 2 -), functions as an intravascular endocrine reservoir of NO bioactivity that can be reduced back to NO under physiological and pathological hypoxia. Critical Issues: The conversion of nitrite to NO is controlled by coupled electron and proton transfer reactions between heme-and molybdenum-containing proteins, such as hemoglobin and xanthine oxidase, and by simple protonation and disproportionation, and possibly by catalyzed disproportionation. The two major sources of nitrite (and nitrate) are the endogenous l-arginine-NO pathway, by oxidation of NO, and the diet, with conversion of nitrate from diet into nitrite by oral commensal bacteria. In the current article, we review the enzymatic formation of nitrite and the available data regarding its use as a therapy for PAH and other cardiovascular diseases. Future Directions: The successful efficacy demonstrated in several animal models and safety in early clinical trials suggest that nitrite may represent a promising new therapy for PAH.

Nitrite Reductase and Nitric-oxide Synthase Activity of the Mitochondrial Molybdopterin Enzymes mARC1 and mARC2

“…Nitrate reduction to nitrite primarily requires commensal oral bacteria that express nitrate reductase enzymes (3). Nitrite reduction can be catalyzed by the mammalian mitochondria (4,5) and several enzymatic nitrite reductase systems (6,7). Determination of the mammalian nitrite reductase pathways is of great interest for human health and disease, as the effects of nitrite are largely mediated by its reduction to NO (2).…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…•2 ) and hydrogen peroxide (H 2 O 2 )] having come into focus over the last decade with conclusive work demonstrating an equally important role in cellular communication (reviewed by Ronson et al, 1999;Wolin, 2000;Ignarro, 2002;Ardanaz and Pagano, 2006;Bian et al, 2008;Touyz et al, 2011;Sparacino-Watkins et al, 2012;Bueno et al, 2013). How these molecules are regulated by signaling microdomains is discussed below, as well as potential contributions from carbon monoxide (CO) and hydrogen sulfide (H 2 S).…”

More answers to the still unresolved question of nitrate tolerance

“…SMC, smooth muscle cell (adapted from ref. 55 with permission). (B) Nitrite is not subject to tolerance formation in non-human primates.…”