Combination of Angiotensin II and L-N G -Nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure.

Dale J., Hamilton, Aijun, Zhang, Shumin, Li, Tram N, Cao, Jessie A, Smith, Indira, Vedula, Andrea M., Cordero-Reyes, Keith A., Youker, Guillermo, Torre-Amione, Anisha A., Gupte

American Journal of Physiology - Heart and Circulatory Physiology |

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-NG-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. mito