PloS one, 2012-09, Vol.7 (9), p.e46549-e46549
2012
Details
- Autor(en) / Beteiligte
- Titel
- Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia
- Ist Teil von
- PloS one, 2012-09, Vol.7 (9), p.e46549-e46549
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0046549Titel-ID: cdi_plos_journals_1326552987
- Format
- –
- Schlagworte
- Aging, Aldehyde reductase, Aldehyde Reductase - biosynthesis, Aldehyde Reductase - genetics, Aldehyde Reductase - physiology, Aldose reductase, Animals, Apoptosis, Biology, Cardiomyocytes, Cardiomyopathy, Ceramides - metabolism, Complications, Dehydrogenases, Development and progression, Diabetes, Diabetes mellitus, Fatty acids, Fatty Acids - metabolism, Fibrosis, Fibrosis - enzymology, Fructose, Fructose - metabolism, Gene expression, Genetic aspects, Glucose, Glucose - metabolism, Heart diseases, Heart failure, Heart Failure - diagnostic imaging, Heart Failure - enzymology, Heart Failure - physiopathology, Heart function, Humans, Ischemia, Kinases, Lipid Metabolism, Medicine, Metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Muridae, Myocardial Ischemia - diagnostic imaging, Myocardial Ischemia - enzymology, Myocardial Ischemia - physiopathology, Myocardium - enzymology, Myocardium - metabolism, Myocardium - pathology, Myocytes, Cardiac - enzymology, Myosin, Myosin Heavy Chains - genetics, Oxidation, Oxidation-Reduction, Oxidative stress, Peroxisome proliferator-activated receptors, Pharmacology, Physiological aspects, PPAR alpha - genetics, Promoter Regions, Genetic, Reactive oxygen species, Reactive Oxygen Species - metabolism, Recovery, Recovery of Function, Reperfusion, Reperfusion Injury - enzymology, Reperfusion Injury - physiopathology, Risk factors, Rodents, Signal transduction, Studies, Transgenic animals, Transgenic mice, Ultrasonography