Aldose reductase activation is a key component of myocardial response to ischemia.
Aldose reductase, a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications in diabetes. Despite recent studies from our laboratory demonstrating protection of ischemic hearts by an aldose reductase inhibitor, the presence and influence of aldose reductase in cardiac tissue remain unknown. Our goal in this study was to isolate and characterize the kinetic properties of cardiac aldose reductase, as well as to study the impact of flux via this enzyme on glucose metabolism and contractile function in hearts subjected to ischemia-reperfusion. Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide. The kinetic parameter of cardiac aldose reductase (Kcat) was significantly higher in ischemic tissues. Aldose reductase inhibition increased glycolysis and glucose oxidation. Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function. These findings indicate that aldose reductase is a component of ischemic injury and that pharmacological inhibitors of aldose reductase present a novel adjunctive approach for protecting ischemic hearts.
Hwang
Yuying C
YC
Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Sato
Sanai
S
Tsai
Jen-Yue
JY
Yan
ShiDu
S
Bakr
Soliman
S
Zhang
Huiping
H
Oates
Peter J
PJ
Ramasamy
Ravichandran
R
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010793:Phthalazines; C110881:S-nitro-N-acetylpenicillamine; D013844:Thiazoles; C067172:zopolrestat; D009569:Nitric Oxide; D000449:Aldehyde Reductase; D010396:Penicillamine; D005947:Glucose