Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia

PLoS One. 2012;7(9):e46549. doi: 10.1371/journal.pone.0046549. Epub 2012 Sep 27.


Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α-myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Reductase / biosynthesis
  • Aldehyde Reductase / genetics
  • Aldehyde Reductase / physiology*
  • Animals
  • Apoptosis
  • Ceramides / metabolism
  • Fatty Acids / metabolism
  • Fibrosis / enzymology
  • Fructose / metabolism
  • Glucose / metabolism
  • Heart Failure / diagnostic imaging
  • Heart Failure / enzymology*
  • Heart Failure / physiopathology
  • Humans
  • Lipid Metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / enzymology*
  • Myocardial Ischemia / physiopathology
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / enzymology*
  • Myosin Heavy Chains / genetics
  • Oxidation-Reduction
  • PPAR alpha / genetics
  • Promoter Regions, Genetic
  • Reactive Oxygen Species / metabolism
  • Recovery of Function
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / physiopathology
  • Ultrasonography


  • Ceramides
  • Fatty Acids
  • PPAR alpha
  • Reactive Oxygen Species
  • Fructose
  • Aldehyde Reductase
  • Myosin Heavy Chains
  • Glucose