title: Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats.
abstract: Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H₂O₂-producing Nox4 increased 40-100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50-70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60-70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.
authors.affiliation: Department of Molecular and Cellular Biology, School of Natural Sciences, University of California Merced, Merced, California;
authors.forename: José Pablo
authors.initials: JP
authors.lastname: Vázquez-Medina
authors.forename: Irina
authors.initials: I
authors.lastname: Popovich
authors.forename: Max A
authors.initials: MA
authors.lastname: Thorwald
authors.forename: Jose A
authors.initials: JA
authors.lastname: Viscarra
authors.forename: Ruben
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Jose G
authors.initials: JG
authors.lastname: Sonanez-Organis
authors.forename: Lisa
authors.initials: L
authors.lastname: Lam
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Rudy M
authors.initials: RM
authors.lastname: Ortiz
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D005979:Glutathione Peroxidase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C002744:3-nitrotyrosine; D014443:Tyrosine; C437965:olmesartan; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D002950:Citrate (si)-Synthase; C027576:4-hydroxy-2-nonenal
keywords: NADPH oxidase; Nrf2; metabolic syndrome