Perlman, David H., Bauer, Selena M., Ashrafian, Houman, Bryan, Nathan S., Garcia-Saura, Maria F., Lim, Chee C., Fernandez, Bernadette O., Infusini, Giuseppe, McComb, Mark E., Costello, Catherine E. and Feelisch, Martin. (2009) Mechanistic insights into nitrite-induced cardioprotection using an integrated metabolomic/proteomic approach. Circulations Research, Vol.104 (No.6). pp. 796-804. ISSN 0009-7330

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Abstract

Nitrite has recently emerged as an important bioactive molecule, capable of conferring cardioprotection and a variety of other benefits in the cardiovascular system and elsewhere. The mechanisms by which it accomplishes these functions remain largely unclear. To characterize the dose response and corresponding cardiac sequelae of transient systemic elevations of nitrite, we assessed the time course of oxidation/nitros(yl)ation, as well as the metabolomic, proteomic, and associated functional changes in rat hearts following acute exposure to nitrite in vivo. Transient systemic nitrite elevations resulted in: (1) rapid formation of nitroso and nitrosyl species; (2) moderate short-term changes in cardiac redox status; (3) a pronounced increase in selective manifestations of long-term oxidative stress as evidenced by cardiac ascorbate oxidation, persisting long after changes in nitrite-related metabolites had normalized; (4) lasting reductions in glutathione oxidation (GSSG/GSH) and remarkably concordant nitrite-induced cardioprotection, which both followed a complex dose-response profile; and (5) significant nitrite-induced protein modifications (including phosphorylation) revealed by mass spectrometry-based proteomic studies. Altered proteins included those involved in metabolism (eg, aldehyde dehydrogenase 2, ubiquinone biosynthesis protein CoQ9, lactate dehydrogenase B), redox regulation (eg, protein disulfide isomerase A3), contractile function (eg, filamin-C), and serine/threonine kinase signaling (eg, protein kinase A R1 alpha, protein phosphatase 2A A R1-alpha). Thus, brief elevations in plasma nitrite trigger a concerted cardioprotective response characterized by persistent changes in cardiac metabolism, redox stress, and alterations in myocardial signaling. These findings help elucidate possible mechanisms of nitrite-induced cardioprotection and have implications for nitrite dosing in therapeutic regimens. (Circ Res. 2009; 104: 796-804.)

Item Type:	Journal Article
Subjects:	Q Science > QM Human anatomy R Medicine > RB Pathology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Circulations Research
Publisher:	Lippincott Williams & Wilkins
ISSN:	0009-7330
Date:	27 March 2009
Volume:	Vol.104
Number:	No.6
Number of Pages:	28
Page Range:	pp. 796-804
Identification Number:	10.1161/CIRCRESAHA.108.187005
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	NIH, National Heart, Lung, and Blood Institute
Grant number:	P41 RR10888, S10 RR15942, S10 RR20946, R01 HL69029, R21 DA020644, N01HV28178
URI:	http://wrap.warwick.ac.uk/id/eprint/28255

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