Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2008

Open Access 01-12-2008 | Original investigation

Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts

Authors: Qing Li, Yuying C Hwang, Radha Ananthakrishnan, Peter J Oates, Dennis Guberski, Ravichandran Ramasamy

Published in: Cardiovascular Diabetology | Issue 1/2008

Login to get access

Abstract

We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients.
Appendix
Available only for authorised users
Literature
1.
Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O'Keefe J, Hartzler GO, Overlie P, Donohue B, Chelliah N, Timmis GC, Vliestra R, Strezelecki M, Puchrowicz-Ochocki S, O'Neill WW: Predictors of in-hospital and 6-minth outcome after acute myocardial infarction in the reperfusion era: the primary angioplasty in myocardial infarction (PAMI) trial. J Am Coll Cardiol. 1995, 25: 370-377. 10.1016/0735-1097(94)00367-Y.CrossRefPubMed
2.
Garcia MJ, McNamara PM, Grodon T, Kannal WB: Morbidity and mortality in the Framingham population: sixteenyear follow-up study. Diabetes. 1974, 23: 105-111.CrossRefPubMed
3.
Jaffe AS, Spadaro JJ, Schetman R, Roberts R, Geltman EM, Sobel BE: Increased congestive heart failure after myocardial infarction of moderate extent in patients with diabetes mellitus. Am Heart J. 1984, 108: 31-37. 10.1016/0002-8703(84)90541-6.CrossRefPubMed
4.
Lehto S, Pyorala K, Miettinen H, Ronnemaa T, Palomaki P, Tuomilehto J, Laakso M: Myocardial infarct size and mortality in patients with non- insulin-dependent diabetes mellitus. J Intern Med. 1994, 236 (3): 291-297.CrossRefPubMed
5.
Woodfield SL, Lundergan CF, Reiner JS, Greenhouse SW, Thompson MA, Rohrbeck SC, Deychak Y, Simoons ML, Califf RM, Topol EJ, Ross AM: Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-1 experience. J Am Coll Cardiol. 1996, 28: 1661-1669. 10.1016/S0735-1097(96)00397-X.CrossRefPubMed
6.
Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anverse P: Myocardial cell death in human diabetes. Circ Res. 2000, 87: 1123-1132.CrossRefPubMed
7.
Shedaheh A, Regan TJ: Cardiac consequences of diabetes mellitus. Clin Cardiol. 1995, 18: 301-305.CrossRef
8.
Anzawa R, Seki S, Horikoshi K, Taniguchi M, Mochizuki S: Exacerbation of acidosis during ischemia and reperfusion arrhythmia in hearts from type 2 Diabetic Otsuka Long-Evans Tokushima Fatty rats. Cardiovasc Diabetol. 2007, 6: 17-10.1186/1475-2840-6-17.PubMedCentralCrossRefPubMed
9.
Wang P, Chatham JC: Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart. Am J Physiol Endocrinol Metab. 2004, 286: E725-736. 10.1152/ajpendo.00295.2003.CrossRefPubMed
10.
Chandler MP, Morgan EE, McElfresh TA, Kung TA, Rennison JH, Hoit BD, Young ME: Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol Heart Circ Physiol. 2007, 293: H1609-1616. 10.1152/ajpheart.01338.2006.CrossRefPubMed
11.
Desrois M, Sidell RJ, Gauguier D, King LM, Radda GK, Clarke K: Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res. 2004, 61: 288-296. 10.1016/j.cardiores.2003.11.021.CrossRefPubMed
12.
Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A: Ischemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes. Diabetologia. 2004, 47: 1716-1721. 10.1007/s00125-004-1514-4.CrossRefPubMed
13.
Ellis EA, Guberski DL, Somogyi-Mann M, Grant MB: Increased H2O2, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. Free Radical Biology Medicine. 2000, 28: 91-101. 10.1016/S0891-5849(99)00216-6.CrossRefPubMed
14.
Sima AAF, Zhang W, Sugimoto K, Guberski DL, Yorek BM: A comparison of diabetic polyneuropathy in Type 2 diabetic BBZDR/Wor rats and in Type 1 diabetic BB/Wor rats. Diabetologia. 2000, 43: 786-793. 10.1007/s001250051376.CrossRefPubMed
15.
Tirabassi RS, Flanagan JF, Wu T, Kislauskis EH, Birckbichler PJ, Guberski DL: The BBZDR/Wor rat model for investigating the complications of type 2 diabetes mellitus. ILAR J. 2004, 45: 292-302.CrossRefPubMed
16.
Harrison DH, Bohren KM, Ringe D, Petsko GA, Gabbay KH: An anion binding site in human aldose reductase: Mechanistic implications for the binding of citrate, cacodylate, and glucose-6-phosphate. Biochemistry. 1994, 33: 2011-2020. 10.1021/bi00174a006.CrossRefPubMed
17.
Busik JV, Hootman SR, Greenidge CA, Henry DN: Glucose-specific regulation of aldose reductase in Capan-1 human pancreatic duct cells in vitro. J Clin Invest. 1997, 100: 1685-1692. 10.1172/JCI119693.PubMedCentralCrossRefPubMed
18.
Srivastava SK, Ansari NH, Hair GA, Awasthi S, Das B: Activation of human erythrocyte, brain, aorta, muscle, and occular tissue aldose reductase. Metabolism. 1986, 35: 114-118. 10.1016/0026-0495(86)90199-X.CrossRefPubMed
19.
Grimshaw CE, Bohren KM, Lai CJ, Gabbay KH: Human aldose reductase: pK of tyrosine 48 reveals the preferred ionization state for catalysis and inhibition. Biochemistry. 1995, 34: 14374-14384. 10.1021/bi00044a014.CrossRefPubMed
20.
Grimshaw CE, Bohren KM, Lai CJ, Gabbay KH: Human aldose reductase: subtle effects revealed by rapid kinetic studies of the C298A mutant enzyme. Biochemistry. 1995, 34: 14366-14373. 10.1021/bi00044a013.CrossRefPubMed
21.
Ramasamy R, Oates PJ: Aldose reductase and vascular stress. Text Book of Diabetes Mellitus and Cardiovascular Disease. Edited by: Marso SP, Stern DM. 2003, Lippincott Williams & Wilkins, Philadelphia, USA, 55-74.
22.
Kador PF, Kinoshita JH: Role of aldose reductase in the development of diabetes associated complications. Am J Med. 1985, 79: 8-12. 10.1016/0002-9343(85)90504-2.CrossRefPubMed
23.
Kador PF: The role of aldose reductase in the development of diabetic complications. Med Res Rev. 1988, 8: 325-352. 10.1002/med.2610080302.CrossRefPubMed
24.
25.
Kinoshita JH, Nishimura C: The involvement of aldose reductase in diabetic complications. Diabetes Metab Rev. 1988, 4: 323-337.CrossRefPubMed
26.
Greene DA, Sima AAF, Stevens MJ, Feldman EL, Killen PD, Henry DN, Thomas T, Dananberg J, Lattimer SA: Aldose reductase inhibitors: an approach to the treatment of diabetic nerve damage. Diabetes Metab Rev. 1993, 9: 189-217.CrossRefPubMed
27.
Ramasamy R, Oates PJ, Schaefer S: Aldose reductase inhibition protects diabetic and non-diabetic rat hearts from ischemic injury. Diabetes. 1997, 46: 292-300. 10.2337/diabetes.46.2.292.CrossRefPubMed
28.
Ramasamy R, Trueblood NA, Schaefer S: Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion. Am J Physiol. 1998, 275: H195-H203.PubMed
29.
Ramasamy R, Hwang YC, hang J, Bergmann SR: Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4. Am J Physiol Heart Circ Physiol. 2001, 281 (1): H290-H297.PubMed
30.
Ramasamy R, Hwang YC, Bakr S, Bergmann SR: Protection of ischemic hearts perfused with an anion exchange inhibitor, DIDS, is associated with beneficial changes in substrate metabolism. Cardiovasc Res. 2001, 51: 275-282. 10.1016/S0008-6363(01)00301-7.CrossRefPubMed
31.
Inskeep PB, Reed AE, Ronfeld RA: Pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, in normal and diabetic rats. Pharmaceut Res. 1991, 8: 1511-1515. 10.1023/A:1015894300247.CrossRef
32.
Hwang YC, Kaneko M, Bakr S, Liao H, Lu Y, Lewis ER, Yan SD, Ii S, Itakura M, Rui L, Skopicki H, Homma S, Schmidt AM, Oates PJ, Szabolcs M, Ramasamy R: Central role for aldose reductase pathway in myocardial ischemic injury. FASEB J. 2004, 18: 1192-1199. 10.1096/fj.03-1400com.CrossRefPubMed
33.
Hwang YC, Sato S, Tsai JY, Bakr S, Yan SD, Oates PJ, Ramasamy R: Aldose reductase activation is a key component of myocardial response to ischemia. FASEB. 2002, 16: 243-245. 10.1096/fj.01-0732com.CrossRef
34.
Hwang YC, Bakr S, Ellery CR, Oates PJ, Ramasamy R: Sorbitol dehydrogenase: A novel target for adjunctive protection of ischemic myocardium. FASEB J. 2003, 17: 2331-2333.PubMed
35.
Trueblood NA, Ramasamy R: Aldose reductase inhibition improves the altered glucose metabolism of isolated diabetic rat hearts. Am J Physiol. 1998, 275: H75-H83.PubMed
36.
Tekin D, Xi L, Zhao T, Tejero-Taldo MI, Atluri S, Kukreja RC: Mitogen-activated protein kinases mediate heat shock induced delayed protection in mouse heart. Am J Physiol Heart Circ Physiol. 2001, 281 (2): H523-H532.PubMed
37.
Peterson RG, Shaw WN, Neel MA, Little LA, Eichberg J: Zucker diabetic fatty rat asa model for non-insulin-dependent diabetes mellitus. ILAR News. 1990, 32: 16-19.CrossRef
38.
Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA. 2000, 97: 1784-1789. 10.1073/pnas.97.4.1784.PubMedCentralCrossRefPubMed
39.
Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, Enden Van den M, ilo C, Tilton RG: Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993, 42: 801-813. 10.2337/diabetes.42.6.801.CrossRefPubMed
40.
Tilton RG, Baier LD, Harlow JE, Smith SR, Ostrow E, Williamson JR: Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+. Kidney Int. 1992, 41: 778-788. 10.1038/ki.1992.121.CrossRefPubMed
41.
Obrosova I, Faller A, Burgan J, Ostrow E, Williamson JR: Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor. Curr Eye Res. 1997, 16: 34-43. 10.1076/ceyr.16.1.34.5113.CrossRefPubMed
42.
Schmidt RE, Dorsey DA, Beaudet LN, Parvin CA, Yarasheski KE, Smith SR, Williamson JR, Peterson RG, Oates PJ: A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. Experimental Neurology. 2005, 192: 407-419. 10.1016/j.expneurol.2004.12.018.CrossRefPubMed
43.
Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA, Yarasheski KE, Smith SR, Lang H, Williamson JR, Ido Y: Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes. J Neuropathol Exp Neurol. 2001, 60 (12): 1153-1169.PubMed
44.
Steenbergen C, Murphy E, Watts JA, London RE: Correlation between cystolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res. 1990, 66: 135-146.CrossRefPubMed
45.
Steenbergen C, Perlman ME, London RE, Murphy E: Mechanism of preconditioning: ionic alterations. Circ Res. 1993, 72: 112-125.CrossRefPubMed
46.
Ramasamy R, Liu H, Anderson S, Lundmark J, Schaefer S: Ischemic preconditioning stimulates sodium and proton transport in the isolated rat heart. J Clin Invest. 1995, 96: 1464-1472. 10.1172/JCI118183.PubMedCentralCrossRefPubMed
47.
Anderson SE, Murphy E, Steenbergen C, London RE, Cala PM: Na-H exchange in myocardium: effects of hypoxia and acidification on Na and Ca. Am J Physiol. 1990, 259: C940-C948.PubMed
48.
Ramasamy R, Liu H, Oates PJ, Schaefer S: Attenuation of ischemia induced increases in sodium and calcium by an aldose reductase inhibitor zopolrestat. Cardiovasc Res. 1999, 42: 130-139. 10.1016/S0008-6363(98)00303-4.CrossRefPubMed
49.
Ramasamy R, Schaefer S: Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: insight into altered susceptibility of diabetic hearts to ischemic injury. J Mol Cell Cardiol. 1999, 31: 785-797. 10.1006/jmcc.1998.0908.CrossRefPubMed
50.
Yue TL, Bao W, Gu JL, Cui J, Tao L, Ma XL, Ohlstein EH, Jucker BM: Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes. 2005, 54: 554-562. 10.2337/diabetes.54.2.554.CrossRefPubMed
51.
Iwata K, Matsuno K, Nishinaka T, Persson C, Yabe-Nishimura C: Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism. J Pharmacol Sci. 2006, 102 (1): 37-46. 10.1254/jphs.FP0060218.CrossRefPubMed
52.
Tracey WR, Magee WP, Ellery CA, MacAndrew JT, Smith AH, Knight DR, Oates PJ: Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury. Am J Physiol Heart Circ Physiol. 2000, 279 (4): H1447-1452.PubMed
53.
Johansen JS, Harris AK, Rychly DJ, Ergul A: Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 4 (1): 5-10.1186/1475-2840-4-5. 2005 Apr 29
Metadata
Title
Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts
Authors
Qing Li
Yuying C Hwang
Radha Ananthakrishnan
Peter J Oates
Dennis Guberski
Ravichandran Ramasamy
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2008
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-7-33

Other articles of this Issue 1/2008

Cardiovascular Diabetology 1/2008 Go to the issue

Original investigation

Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample

Original investigation

Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats

Original investigation

Dyslipidemia in primary care – prevalence, recognition, treatment and control: data from the German Metabolic and Cardiovascular Risk Project (GEMCAS)

Original investigation

Eptifibatide and abciximab inhibit insulin-induced focal adhesion formation and proliferative responses in human aortic smooth muscle cells

Original investigation

Uteroplacental insufficiency down regulates insulin receptor and affects expression of key enzymes of long-chain fatty acid (LCFA) metabolism in skeletal muscle at birth

Original investigation

Association between intrarenal arterial resistance and diastolic dysfunction in type 2 diabetes
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits