HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/C928    most recent 00045.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wu, C. Articles by Vatner, D. E. PubMed PubMed Citation Articles by Wu, C. Articles by Vatner, D. E.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction

Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, Univeristy of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

Submitted 22 January 2009 ; accepted in final form 14 July 2009

Cytochrome c oxidase (COX) is composed of 13 subunits, of which COX I, II, and III are encoded by a mitochondrial gene. COX I and II function as the main catalytic components, but the function of COX III is unclear. Because myocardial ischemia affects mitochondrial oxidative metabolism, we hypothesized that COX activity and expression would be affected during postischemic cardiomyopathy. This hypothesis was tested in a monkey model following myocardial infarction (MI) and subsequent pacing-induced heart failure (HF). In this model, COX I protein expression was decreased threefold after MI and fourfold after HF (P < 0.05 vs. sham), whereas COX II expression remained unchanged. COX III protein expression increased 5-fold after MI and further increased 10-fold after HF compared with sham (P < 0.05 vs. sham). The physiological impact of COX III regulation was examined in vitro. Overexpression of COX III in mitochondria of HL-1 cells resulted in an 80% decrease in COX I, 60% decrease in global COX activity, 60% decrease in cell viability, and threefold increase in apoptosis (P < 0.05). Oxidative stress induced by H₂O₂ significantly (P < 0.05) increased COX III expression. H₂O₂ decreased cell viability by 47 ± 3% upon overexpression of COX III, but only by 12 ± 5% in control conditions (P < 0.05). We conclude that ischemic stress in vivo and oxidative stress in vitro lead to upregulation of COX III, followed by downregulation of COX I expression, impaired COX oxidative activity, and increased apoptosis. Therefore, upregulation of COX III may contribute to the increased susceptibility to apoptosis following MI and subsequent HF.

cytochrome oxidase; mitochondria; myocardial ischemia; oxidative stress