title: Mechanistic insights into nitrite-induced cardioprotection using an integrated metabolomic/proteomic approach.
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 R1alpha, 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.
authors.affiliation: Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Perlman
authors.forename: Selena M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Houman
authors.initials: H
authors.lastname: Ashrafian
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.forename: Maria F
authors.initials: MF
authors.lastname: Garcia-Saura
authors.forename: Chee C
authors.initials: CC
authors.lastname: Lim
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Infusini
authors.forename: Mark E
authors.initials: ME
authors.lastname: McComb
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009573:Nitrites / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D009124:Muscle Proteins; D009573:Nitrites; D020543:Proteome