Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways.
We previously reported that hydrogen sulfide (H(2)S) preconditioning (SP) produces cardioprotective effects against ischemia in rat cardiac myocytes. The present study aims to elucidate the signaling mechanisms involved in SP-induced cardioprotection by investigating the role of extracellular signal regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt. We found that preconditioning with NaHS (a H(2)S donor) for three cycles significantly decreased myocardial infarct size and improved heart contractile function in the isolated rat hearts. NaHS (1-100 microM) concentration-dependently increased cell viability and percentage of rod-shaped cardiac myocytes. Blockade of ERK1/2 with PD 98059 or PI3K/Akt with LY-294002 or Akt inhibitor III during either preconditioning or ischemia periods significantly attenuated the cardioprotection of SP, suggesting that both ERK1/2 and PI3K/Akt triggered and mediated the cardioprotection of SP. Moreover, SP induced ERK1/2 and Akt phosphorylation in isolated hearts. The phosphorylation of ERK1/2 induced by SP was attenuated by either glibenclamide, an ATP-sensitive K(+) channel (K(ATP)) blocker, or chelerythrine, a specific protein kinase C (PKC) blocker. In addition, ischemic-preconditioning-induced ERK1/2 activation was reversed by inhibiting endogenous H(2)S production, suggesting that ERK1/2 activation induced by ischemic preconditioning was, at least partly, mediated by endogenous H(2)S. In conclusion, K(ATP)/PKC/ERK1/2 and PI3K/Akt pathways contributed to SP-induced cardioprotection.
Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Yeshi
Y
Hu
Xin
X
Chen
Ting-Ting
TT
Pan
Kay Li
KL
Neo
Shiau Wei
SW
Lee
Ester Sandar Win
ES
Khin
Philip K
PK
Moore
Jin-Song
JS
Bian
D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D005905:Glyburide; D006862:Hydrogen Sulfide; D054086:KATP Channels; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013440:Sulfides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C016299:chelerythrine; C025451:sodium bisulfide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one