Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases.
Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organ protect the target organ against sustained ischemia-reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning (RRPC) are well established in heart, but their mechanisms still remain to be elucidated. So, the present study was designed to investigate the possible role of oxygen-sensing hypoxia inducible factor-prolyl 4-hydroxylases (HIF-P4Hs) in RRPC-induced cardioprotection in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion and reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Ethyl 3,4-dihydroxybenzoate (EDHB) and alpha-ketoglutarate (alpha-KG) were employed as HIF-P4Hs inhibitor and activator, respectively. Diethyldithiocarbamic acid (DDCA) was employed as NFkB inhibitor. Remote renal preconditioning prevented I/R-induced myocardial injury and produced cardioprotective effects. Pharmacological preconditioning with EDHB (100 mg kg(-1) i.p.) mimicked the cardioprotective effects of RRPC. However, alpha-KG (200 mg kg(-1) i.p.) and DDCA (150 mg kg(-1) i.p.) abolished cardioprotective effects of RRPC and EDHB. So, it may be concluded that inhibition of HIF-P4H has a key role in RRPC-induced cardioprotection. Further, remote preconditioning-induced HIF-P4H inhibition may have triggered a transduction pathway involving activation of NFkB.
Kant
Ravi
R
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India.
Diwan
Vishal
V
Jaggi
Amteshwar Singh
AS
Singh
Nirmal
N
Singh
Dhandeep
D
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D003402:Creatine Kinase / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004050:Ditiocarb / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D062385:Hydroxybenzoates / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D019194:Ischemic Preconditioning / Q000379:methods*; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects
C497444:Hif1a protein, rat; D062385:Hydroxybenzoates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; C018063:ethyl protocatechuate; D004050:Ditiocarb; D007770:L-Lactate Dehydrogenase; D011393:Procollagen-Proline Dioxygenase; D003402:Creatine Kinase