Cardiomyocyte aldose reductase causes heart failure and impairs recovery from
Authors Son NH, Ananthakrishnan R, Yu S, Khan RS, Jiang H, Ji R, Akashi H, Li Q, O'Shea
K, Homma S, Goldberg IJ, Ramasamy R
Submitted By Submitted Externally on 3/4/2015
Status Published
Journal PLoS ONE
Year 2012
Date Published
Volume : Pages 7 : e46549
PubMed Reference 23029549
Abstract 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 a-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.

Investigators with authorship
Ira GoldbergNew York University School of Medicine