Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts.
OBJECTIVE
Coupling of glucose oxidation to glycolysis is lower in hypertrophied than in non-hypertrophied hearts, contributing to the compromised mechanical performance of hypertrophied hearts. Here, we describe studies to test the hypothesis that low coupling of glucose oxidation to glycolysis in hypertrophied hearts is due to reduced activity and/or expression of the pyruvate dehydrogenase complex (PDC).


METHODS
We examined the effects of dichloroacetate (DCA), an inhibitor of PDC kinase, and of alterations in exogenous palmitate supply on coupling of glucose oxidation to glycolysis in isolated working hypertrophied and control hearts from aortic-constricted and sham-operated male Sprague-Dawley rats. It was anticipated that the addition of DCA or the absence of palmitate would promote PDC activation and consequently normalize coupling between glycolysis and glucose oxidation in hypertrophied hearts if our hypothesis was correct.


RESULTS
Addition of DCA or removal of palmitate improved coupling of glucose oxidation to glycolysis in control and hypertrophied hearts. However, coupling remained substantially lower in hypertrophied hearts. PDC activity in extracts of hypertrophied hearts was similar to or higher than in extracts of control hearts under all perfusion conditions. No differences were observed between hypertrophied and control hearts with respect to expression of PDC, PDC kinase, or PDC phosphatase.


CONCLUSIONS
Low coupling of glucose oxidation to glycolysis in hypertrophied hearts is not due to a reduction in PDC activity or subunit expression indicating that other mechanism(s) are responsible.
Lydell
Carmen P
CP
McDonald Research Laboratories/The iCapture Centre, Department of Pathology and Laboratory Medicine, Room 292, University of British Columbia-St. Paul's Hospital, 1081 Burrand Street, Vancouver, BC, Canada V6Z 1Y6.
Chan
Andy
A
Wambolt
Richard B
RB
Sambandam
Nandakumar
N
Parsons
Hannah
H
Bondy
Gregory P
GP
Rodrigues
Brian
B
Popov
Kirill M
KM
Harris
Robert A
RA
Brownsey
Roger W
RW
Allard
Michael F
MF
D000818:Animals; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; D005947:Glucose