Central role for aldose reductase pathway in myocardial ischemic injury.
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.
Hwang
Yuying C
YC
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Kaneko
Michiyo
M
Bakr
Soliman
S
Liao
Hui
H
Lu
Yan
Y
Lewis
Erin R
ER
Yan
Shidu
S
Ii
Setsuko
S
Itakura
Mitsuo
M
Rui
Liu
L
Skopicki
Hal
H
Homma
Shunichi
S
Schmidt
Ann Marie
AM
Oates
Peter J
PJ
Szabolcs
Matthias
M
Ramasamy
Ravichandran
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003331:Coronary Vessels; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D007064:L-Iditol 2-Dehydrogenase / Q000494:pharmacology; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016277:Ventricular Function, Left
D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D009243:NAD; D009525:Niacin; D019308:Palmitic Acid; D000255:Adenosine Triphosphate; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase; D005947:Glucose