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Central role for aldose reductase pathway in myocardial ischemic injury.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2004 Aug; Vol. 18 (11), pp. 1192-9. - Publication Year :
- 2004
-
Abstract
- Aldose reductase (AR), a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications of diabetes. Recently, we demonstrated that aldose reductase is a component of myocardial ischemic injury and that inhibitors of this enzyme protect rat hearts from ischemia-reperfusion injury. To rigorously test the effect of aldose reductase on myocardial ischemia-reperfusion injury, we used transgenic mice broadly overexpressing human aldose reductase (ARTg) driven by the major histocompatibility complex I promoter. Hearts from these ARTg or littermate mice (WT) (n=6 in each group) were isolated, perfused under normoxic conditions, then subjected to 50 min of severe low flow ischemia followed by 60 min of reperfusion. Creatine kinase (CK) release (a marker of ischemic injury) was measured during reperfusion; left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and ATP were measured throughout the protocol. CK release was significantly greater in ARTg mice compared with the WT mice. LVDP recovery was significantly reduced in ARTg mice compared with the WT mice. Furthermore, ATP content was higher in WT mice compared with ARTg mice during ischemia and reperfusion. Infarct size measured by staining techniques and myocardial damage evaluated histologically were also significantly worse in ARTg mice hearts than in controls. Pharmacological inhibition of aldose reductase significantly reduced ischemic injury and improved functional recovery in ARTg mice. These data strongly support key roles for AR in ischemic injury and impairment of functional and metabolic recovery after ischemia. We propose that interventions targeting AR may provide a novel adjunctive approach to protect ischemic myocardium.
- Subjects :
- Adenosine Triphosphate metabolism
Aldehyde Reductase antagonists & inhibitors
Aldehyde Reductase biosynthesis
Aldehyde Reductase genetics
Animals
Coronary Vessels
Cytosol metabolism
Enzyme Inhibitors pharmacology
Glucose metabolism
Glycolysis
L-Iditol 2-Dehydrogenase pharmacology
Ligation
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardial Ischemia pathology
Myocardial Reperfusion Injury pathology
Myocardium metabolism
NAD metabolism
Niacin pharmacology
Organ Culture Techniques
Oxidation-Reduction
Palmitic Acid metabolism
Recombinant Fusion Proteins physiology
Ventricular Function, Left
Aldehyde Reductase physiology
Myocardial Ischemia enzymology
Myocardial Reperfusion Injury enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 18
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 15284219
- Full Text :
- https://doi.org/10.1096/fj.03-1400com