title: Mechanism of sphingosine-1-phosphate induced cardioprotection against I/R injury in diabetic rat heart: Possible involvement of glycogen synthase kinase 3β and mitochondrial permeability transition pore.
abstract: There is growing evidence that diabetes mellitus causes attenuation of the bioactive metabolite of membrane sphingolipids, sphingosine-1-phosphate, and this may be a key mechanism in the decreased cardioprotective effect of ischaemic preconditioning (IPC) in the diabetic heart. Thus, this study has been designed to investigate the role and pharmacological potential of sphingosine-1-phosphate in diabetic rat heart. Diabetes was produced in Wistar rats by administration of a low dose of streptozotocin (STZ) (35 mg/kg, i.p., once) and feeding a high fat diet (HFD) for 6 weeks. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pre-ischaemic treatment (before ischaemia for 20 min) and pharmacological preconditioning with the S1P agonist FTY720 (0.6 μmol/L) with and without atractyloside (an mPTP opener; in the last episode of reperfusion before I/R). Myocardial infarction was assessed in terms of increase in lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for assessment of tumour necrosis factor (TNF)-α and glycogen synthase kinase (GSK)-3β level in cardiac tissue. Pre-ischaemic treatment and pharmacological preconditioning with FTY720 significantly decreased I/R-induced myocardial infarction, TNF-alpha, GSK-3β level and release of LDH and CK-MB as compared to control group. The cardioprotective effect of S1P agonist was significantly attenuated by atractyloside. It may be concluded that S1P agonist FTY720 prevents the diabetic heart from ischaemic reperfusion injury, possibly through inhibition of GSK-3β and regulation of opening of mitochondrial permeability transition pore.
authors.affiliation: Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
authors.affiliation: Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D059305:Diet, High-Fat / Q000009:adverse effects; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D019194:Ischemic Preconditioning; D008055:Lipids / Q000097:blood; D008246:Lysophospholipids / Q000819:agonists*; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives*
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D008055:Lipids; D008246:Lysophospholipids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C060506:sphingosine 1-phosphate; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D052279:Creatine Kinase, MB Form; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: FTY720; diabetes mellitus; ischaemic preconditioning; ischaemic reperfusion injury; sphingosine-1-phosphate