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Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l- N<jats:sup>G<\/jats:sup>-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 H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>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.<\/jats:p>","DOI":"10.1152\/ajpheart.00746.2015","type":"journal-article","created":{"date-parts":[[2016,1,9]],"date-time":"2016-01-09T04:13:45Z","timestamp":1452312825000},"page":"H667-H680","source":"Crossref","is-referenced-by-count":28,"title":["Combination of angiotensin II and<scp>l<\/scp>-<i>N<\/i><sup>G<\/sup>-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure"],"prefix":"10.1152","volume":"310","author":[{"given":"Dale J.","family":"Hamilton","sequence":"first","affiliation":[{"name":"Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas;"},{"name":"Houston Methodist Department of Medicine, Weill Cornell Medical College, Houston, 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