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Mechanistic insights into nitrite-induced cardioprotection using an integrated metabolomic/proteomic approach
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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. doi:10.1161/CIRCRESAHA.108.187005
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Official URL: http://dx.doi.org/10.1161/CIRCRESAHA.108.187005
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 | ||||
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| Subjects: | Q Science > QM Human anatomy R Medicine > RB Pathology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Circulations Research | ||||
| Publisher: | Lippincott Williams & Wilkins | ||||
| ISSN: | 0009-7330 | ||||
| Official Date: | 27 March 2009 | ||||
| Dates: |
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| Volume: | Vol.104 | ||||
| Number: | No.6 | ||||
| Number of Pages: | 28 | ||||
| Page Range: | pp. 796-804 | ||||
| DOI: | 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 |
Data sourced from Thomson Reuters' Web of Knowledge
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