Physiological Genomics

Quantitative Proteomic Analysis Reveals Novel Mitochondrial Targets of Estrogen Deficiency in the Aged Female Rat Heart

Timothy L Lancaster, Sarah J. Jefferson, J Craig Hunter, Veronica U. Lopez, Jennifer Van Eyk, Edward G Lakatta, Donna Hope Korzick


The incidence of myocardial infarction rises sharply at the time of menopause, implicating a potential role for estrogen (E2) loss in age-related increases in ischemic injury. Aims: To identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E2 deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Methods and Results: 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 6 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. Conclusions: Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E2 deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic.

  • ischemic heart disease
  • respiration
  • iTRAQ
  • monamine oxidase A
  • cardioprotection