title: Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart.
abstract: The incidence of myocardial infarction rises sharply at menopause, implicating a potential role for estrogen (E(2)) loss in age-related increases in ischemic injury. We aimed to identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E(2) deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary-intact or ovariectomized (OVX) rats were labeled with 8plex isobaric tags for relative and absolute quantification (iTRAQ; n = 5-6/group). Groups studied were adult, adult OVX, aged, and aged OVX. In vivo coronary artery ligation and in vitro mitochondrial respiration studies were also performed in a subset of rats. We identified 965 proteins across groups and significant directional changes in 67 proteins of aged and/or aged OVX; 32 proteins were unique to aged OVX. Notably, only six proteins were similarly altered in adult OVX (voltage-dependent ion channel 1, adenine nucleotide translocator 1, cytochrome c oxidase subunits VIIc and VIc, catalase, and myosin binding protein C). Proteins affected by aging were primarily related to cellular metabolism, oxidative stress, and cell death. The largest change occurred in monoamine oxidase-A (MAO-A), a source of oxidative stress. While acute MAO-A inhibition induced mild uncoupling in aged mitochondria, reductions in infarct size were not observed. Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E(2) deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic intervention in the aged female population.
authors.affiliation: Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Lancaster
authors.forename: S J
authors.initials: SJ
authors.lastname: Jefferson
authors.forename: J Craig
authors.initials: JC
authors.lastname: Hunter
authors.forename: Veronica
authors.initials: V
authors.lastname: Lopez
authors.forename: J E
authors.initials: JE
authors.lastname: Van Eyk
authors.forename: E G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: D H
authors.initials: DH
authors.lastname: Korzick
mesh_terms: D000818:Animals; D004967:Estrogens / Q000172:deficiency* / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D010101:Oxygen Consumption; D040901:Proteomics / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004967:Estrogens; D008995:Monoamine Oxidase