Published online before print February 19, 2009, doi: 10.1161/CIRCRESAHA.108.187005
© 2009 American Heart Association, Inc.
Integrative Physiology |
Mechanistic Insights Into Nitrite-Induced Cardioprotection Using an Integrated Metabolomic/Proteomic Approach
From the Cardiovascular Proteomics Center (D.H.P., G.I., M.E.M., C.E.C.), Center for Biomedical Mass Spectrometry and Whitaker Cardiovascular Institute (S.M.B., N.S.B., M.F.G.-S., C.C.L., B.O.F., M.F.), Boston University School of Medicine, Boston, Mass; and Department of Cardiovascular Medicine (H.A.), Oxford University, United Kingdom. Present address for C.C.L.: Vanderbilt University Medical Center, Nashville, Tenn. Present address for B.O.F. and M.F.: Warwick Medical School, University of Warwick, Coventry, United Kingdom. Present address for N.S.B.: University of Texas—Houston Health Sciences Center, Houston, Tex.
Correspondence to Martin Feelisch, PhD, Professor of Experimental Medicine & Integrative Biology, Warwick Medical School, The University of Warwick, Gibbet Hill Rd, Coventry, CV4 7AL, United Kingdom. E-mail mf{at}warwick.ac.uk
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
, protein phosphatase 2A A R1-). 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.
Key Words: mitochondria • oxidative stress • redox signaling • nitric oxide • preconditioning
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