title: Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure.
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.
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas; Houston Methodist Department of Medicine, Weill Cornell Medical College, Houston, Texas;
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Hamilton
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;
authors.forename: Shumin
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;
authors.forename: Tram N
authors.initials: TN
authors.lastname: Cao
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;
authors.forename: Jessie A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;
authors.forename: Indira
authors.initials: I
authors.lastname: Vedula
authors.affiliation: Houston Methodist Department of Cardiology, Weill Cornell Medical College, Houston, Texas;
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cordero-Reyes
authors.affiliation: Houston Methodist Department of Cardiology, Weill Cornell Medical College, Houston, Texas;
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Houston Methodist Department of Cardiology, Weill Cornell Medical College, Houston, Texas; Catedra de Cardiologia y Medicina Vascular, Tecnologico de Monterrey, Nuevo Leon, Mexico.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas; aagupte@houstonmethodist.org.
authors.forename: Anisha A
authors.initials: AA
authors.lastname: Gupte
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D020097:Natriuretic Peptide, Brain / Q000187:drug effects / Q000235:genetics; D020098:Natriuretic Peptide, C-Type / Q000187:drug effects / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011498:Protein Precursors / Q000187:drug effects / Q000235:genetics; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; C431578:Nppa protein, mouse; D011498:Protein Precursors; D011768:Pyruvate Dehydrogenase Complex; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517672:Camk2b protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D042967:Electron Transport Complex I; C506947:Atp2a2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester
keywords: angiotensin II; heart failure; mitochondria; nitric oxide; oxidative stress