Abstract 12504: Overexpression of Phosphoglycerate Mutase, a Glycolytic Enzyme, Induces Pro-inflammatory Response and Impairs Cardiac Function
Background: Cardiac glucose metabolism changes during the progression of heart failure. However, whether the change is adaptive or maladaptive remains to be elucidated. Phosphoglycerate mutase (PGM) is a glycolytic enzyme, and is also known to regulate the stress resistance of cells. We assessed the hypothesis that PGM regulates cardiac function and stress resistance of the heart.
Methods and Results: To examine the role of PGM in heart failure, we created and characterized transgenic mice overexpressing PGM in a heart-specific manner. Two transgenic lines were obtained with low (6.7-fold compared to wild type) or high (8.4-fold) expression of PGM protein. PGM transgenic lines survived normally up to 12 months. Echocardiographic examination of PGM transgenic mice showed normal findings, but cardiac functional reserve assessed by measuring left ventricular pressure under dobutamine infusion was impaired. Uptake of 18FDG (a glucose analogue) or 125I-9MPA (a fatty acid analogue) did not differ between PGM mice and NTg mice. The heart weight of PGM mice was normal. Microarray analysis showed the expression of genes related to inflammation and metabolism was modified in PGM mice. Upon quantitative PCR analysis, mRNAs of TNFα, IL-1β, and IL-5Rα were increased in PGM mice compared to NTg mice (4.9±1.3 fold, 5.1±1.2 fold, 18.7±3.6 fold compared to NTg mice respectively). The number of interstitial CD3-positive cells was increased in PGM mice, although there was no fibrosis or cell death. To examine the role of PGM in stress resistance of the heart, PGM mice were subjected to transverse aortic constriction (TAC). Systolic function of NTg mice with TAC was preserved, but PGM mice with TAC developed heart failure. Fibrosis was markedly increased in banded PGM mice compared to that in banded NTg mice.
Conclusions: Overexpression of phosphoglycerate mutase, a glycolytic enzyme, induces a pro-inflammatory response and impairs cardiac function in mice.
- © 2010 by American Heart Association, Inc.