Abstract 16479: Cardiomyocyte Aldose Reductase Expression Increases Cardiac Fibrosis and Heart Dysfunction in the Setting of Reduced Fatty Acid Oxidation
Introduction: A switch in energy source from fatty acid (FA) oxidation (FAO) towards glucose oxidation has been implicated in cardiac ischemic injury and dysfunction. Recent investigations suggest that aldose reductase (AR), an enzyme activating the first step in polyol pathway of glucose metabolism, is associated with increased cardiac ischemic injury in rats. We tested the hypothesis that deleterious effects of AR are due to its actions in cardiomyocytes rather than other cardiac cells.
Methods: We created mice with cardiac specific expression of human AR (hAR) via the α-myosin heavy chain (α-MHC) promoter and studied these animals in the setting of reduced FAO.
Results: Six month old MHC-hAR hearts exhibited increased heart tissue fructose content (2.72 ± 0.35 vs. 4.45 ± 0.13 nmol/mg of protein, n=5-7, P <0.05). Hearts from MHC-hAR transgenic mice had increased mRNA levels of sorbitol dehydrogenase gene expression (1.00 ± 0.12 vs. 2.74 ± 0.21, n=7-11, P < 0.01, indicative of increased flux through the polyol pathway) and pyruvate dehydrogenase kinase 4 (1.00 ± 0.14 vs. 1.89 ± 0.11, n=7-11, P < 0.01, suggesting reduced glucose oxidation). However, FAO and transport genes, such as acyl-CoA oxidase and carnitine palmitoyl transferase-1 were reduced by 31% to 27% (n= 7-11, P < 0.01 and < 0.05 respectively). Expression of the heart failure marker brain-type natriuretic peptide (BNP) was increased (1.5-fold, P < 0.05) in MHC-hAR hearts. Neither FA translocase (CD36) nor PPARγ coactivator 1 was altered in MHC-hAR compared to normal control mice. When the MHC-hAR mice were subjected to Langendorff ligation followed by reperfusion, infract size was significantly greater in MHC-hAR mice than in non-transgenic littermates (46±6% vs. 29±5%, P < 0.05). Functional and metabolic recovery was significantly reduced in MHC-hAR mice (22±3% vs 34±5%, P < 0.05). The MHC-hAR transgene was crossed onto the PPAR alpha knockout background to increase glucose use and reduce FAO. The resulting mice developed cardiac dysfunction associated with increased heart cardiac fibrosis, ROS and apoptosis.
Conclusion: Cardiac overexpression of hAR causes cardiac dysfunction and may be a reason for reduced heart function in the setting of diabetes and ischemia.
- © 2011 by American Heart Association, Inc.