Hamilton 2016 Am J Physiol Heart Circ Physiol
|Hamilton DJ, Zhang A, Li S, Cao TN, Smith JA, Vedula I, Cordero-Reyes AM, Youker KA, Torre-Amione G, Gupte AA (2016) Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure. Am J Physiol Heart Circ Physiol 310:H667-80.|
Hamilton DJ, Zhang A, Li S, Cao TN, Smith JA, Vedula I, Cordero-Reyes AM, Youker KA, Torre-Amione G, Gupte AA (2016) Am J Physiol Heart Circ Physiol
Abstract: Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.
Copyright © 2016 the American Physiological Society. • Keywords: Angiotensin II, Heart failure, Mitochondria, Nitric oxide, Oxidative stress, Amplex Red
• O2k-Network Lab: US LA Baton Rouge Hand SC
Labels: MiParea: Respiration, mt-Medicine Pathology: Cardiovascular Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Heart Preparation: Permeabilized tissue, Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: F, N, S, NS, Other combinations, ROX HRR: Oxygraph-2k