Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia.
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....
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2012-01-01
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doaj-966e20a40a4042d0a4ef566495faf45d2020-11-25T00:12:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4654910.1371/journal.pone.0046549Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia.Ni-Huiping SonRadha AnanthakrishnanShuiqing YuRaffay S KhanHongfeng JiangRuiping JiHirokazu AkashiQing LiKaren O'SheaShunichi HommaIra J GoldbergRavichandran RamasamyAldose 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.http://europepmc.org/articles/PMC3459912?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ni-Huiping Son Radha Ananthakrishnan Shuiqing Yu Raffay S Khan Hongfeng Jiang Ruiping Ji Hirokazu Akashi Qing Li Karen O'Shea Shunichi Homma Ira J Goldberg Ravichandran Ramasamy |
spellingShingle |
Ni-Huiping Son Radha Ananthakrishnan Shuiqing Yu Raffay S Khan Hongfeng Jiang Ruiping Ji Hirokazu Akashi Qing Li Karen O'Shea Shunichi Homma Ira J Goldberg Ravichandran Ramasamy Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. PLoS ONE |
author_facet |
Ni-Huiping Son Radha Ananthakrishnan Shuiqing Yu Raffay S Khan Hongfeng Jiang Ruiping Ji Hirokazu Akashi Qing Li Karen O'Shea Shunichi Homma Ira J Goldberg Ravichandran Ramasamy |
author_sort |
Ni-Huiping Son |
title |
Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
title_short |
Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
title_full |
Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
title_fullStr |
Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
title_full_unstemmed |
Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
title_sort |
cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3459912?pdf=render |
work_keys_str_mv |
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