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(Circulation Research. 2008;102:103.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Persistent Regional Downregulation in Mitochondrial Enzymes and Upregulation of Stress Proteins in Swine With Chronic Hibernating Myocardium

Brian Page, Rebeccah Young, Vijay Iyer, Gen Suzuki, Maciej Lis, Lioubov Korotchkina, Mulchand S. Patel, Kenneth M. Blumenthal, James A. Fallavollita, John M. Canty, Jr

From the VA WNY Health Care System, the Center for Research in Cardiovascular Medicine, the Center for Excellence in Bioinformatics and Life Sciences, the Departments of Medicine, Physiology and Biophysics, and Biochemistry at the University at Buffalo, NY.

Correspondence to John M. Canty Jr, MD, Division of Cardiovascular Medicine, University at Buffalo, Biomedical Research Building, Room 361, 3435 Main St, Buffalo, NY 14214. E-mail canty{at}buffalo.edu

Hibernating myocardium is accompanied by a downregulation in energy utilization that prevents the immediate development of ischemia during stress at the expense of an attenuated level of regional contractile function. We used a discovery based proteomic approach to identify novel regional molecular adaptations responsible for this phenomenon in subendocardial samples from swine instrumented with a chronic LAD stenosis. After 3 months (n=8), hibernating myocardium was present as reflected by reduced resting LAD flow (0.75±0.14 versus 1.19±0.14 mL · min^–1 · g^–1 in remote) and wall thickening (1.93±0.46 mm versus 5.46±0.41 mm in remote, P<0.05). Regionally altered proteins were quantified with 2D Differential-in-Gel Electrophoresis (2D-DIGE) using normal myocardium as a reference with identification of candidates using MALDI-TOF mass spectrometry. Hibernating myocardium developed a significant downregulation of many mitochondrial proteins and an upregulation of stress proteins. Of particular note, the major entry points to oxidative metabolism (eg, pyruvate dehydrogenase complex and Acyl-CoA dehydrogenase) and enzymes involved in electron transport (eg, complexes I, III, and V) were reduced (P<0.05). Multiple subunits within an enzyme complex frequently showed a concordant downregulation in abundance leading to an amplification of their cumulative effects on activity (eg, "total" LAD PDC activity was 21.9±3.1 versus 42.8±1.9 mU, P<0.05). After 5-months (n=10), changes in mitochondrial and stress proteins persisted whereas cytoskeletal proteins (eg, desmin and vimentin) normalized. These data indicate that the proteomic phenotype of hibernating myocardium is dynamic and has similarities to global changes in energy substrate metabolism and function in the advanced failing heart. These proteomic changes may limit oxidative injury and apoptosis and impact functional recovery after revascularization.

Key Words: metabolism • proteomics • hibernating myocardium • ischemic heart disease

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