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. 2016 Mar 15;310(6):H667-80. doi: 10.1152/ajpheart.00746.2015. Epub 2016 Jan 8.


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.

Keywords: angiotensin II; heart failure; mitochondria; nitric oxide; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Atrial Natriuretic Factor
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Cardiomegaly
  • DNA, Mitochondrial / drug effects
  • DNA, Mitochondrial / metabolism
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / drug effects
  • Electron Transport Complex II / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression / drug effects
  • Heart / drug effects
  • Heart Failure / etiology*
  • Hydrogen Peroxide / metabolism
  • Mice
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology
  • NG-Nitroarginine Methyl Ester / pharmacology*
  • Natriuretic Peptide, Brain / drug effects
  • Natriuretic Peptide, Brain / genetics
  • Natriuretic Peptide, C-Type / drug effects
  • Natriuretic Peptide, C-Type / genetics
  • Nitric Oxide / metabolism*
  • Oxidative Stress / drug effects*
  • Protein Precursors / drug effects
  • Protein Precursors / genetics
  • Pyruvate Dehydrogenase Complex / drug effects
  • Pyruvate Dehydrogenase Complex / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / drug effects
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Vasoconstrictor Agents / pharmacology*


  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Nppa protein, mouse
  • Protein Precursors
  • Pyruvate Dehydrogenase Complex
  • Vasoconstrictor Agents
  • Angiotensin II
  • Natriuretic Peptide, Brain
  • Natriuretic Peptide, C-Type
  • Nitric Oxide
  • Atrial Natriuretic Factor
  • Hydrogen Peroxide
  • Electron Transport Complex II
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2b protein, mouse
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Electron Transport Complex I
  • Atp2a2 protein, mouse
  • NG-Nitroarginine Methyl Ester