Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium.
Sorbitol dehydrogenase (SDH) is a polyol pathway enzyme that catalyzes conversion of sorbitol to fructose. Recent studies have demonstrated that activation of aldose reductase, the first enzyme of the polyol pathway, is a key response to ischemia and that inhibition of aldose reductase reduces myocardial ischemic injury. In our efforts to understand the role of pathway in affecting metabolism under normoxic and ischemic conditions, as well as in ischemic injury in myocardium, we investigated the importance of SDH by use of a specific inhibitor (SDI), CP-470,711. SDH inhibition increased glucose oxidation, whereas palmitate oxidation remained unaffected. Global ischemia increased myocardial SDH activity by approximately 1.5 fold. The tissue lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, was reduced by SDH inhibition under both normoxic and ischemic conditions. ATP was higher in SDI hearts during ischemia and reperfusion. Creatine kinase release during reperfusion, a marker of myocardial ischemic injury, was markedly attenuated in SDH-inhibited hearts. These data indicate that myocardial SDH activation is a component of ischemic response and that interventions that inhibit SDH protect ischemic myocardium. Furthermore, these data identify SDH as a novel target for adjunctive cardioprotective interventions.
Hwang
Yuying C
YC
Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Bakr
Soliman
S
Ellery
Craig A
CA
Oates
Peter J
PJ
Ramasamy
Ravichandran
R
D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000201:enzymology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D009924:Organ Culture Techniques; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats
C467608:CP-470711; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D007064:L-Iditol 2-Dehydrogenase; D005947:Glucose