title: Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C.
abstract: BACKGROUND
  We and others have reported that transient accumulation of cyclic AMP (cAMP) in the myocardium during ischemic preconditioning (IP) limits infarct size independent of protein kinase C (PKC). Accumulation of cAMP activates protein kinase A (PKA), which has been demonstrated to cause reversible inhibition of RhoA and Rho-kinase. We investigated the involvement of PKA and Rho-kinase in the infarct limitation by IP.
  
  
  RESULTS
  Dogs were subjected to 90-minute ischemia and 6-hour reperfusion. We examined the effect on Rho-kinase activity during sustained ischemia and infarct size of (1) preischemic transient coronary occlusion (IP), (2) preischemic activation of PKA/PKC, (3) inhibition of PKA/PKC during IP, and (4) inhibition of Rho-kinase or actin cytoskeletal deactivation during myocardial ischemia. Either IP or dibutyryl-cAMP treatment activated PKA, which was dose-dependently inhibited by 2 PKA inhibitors (H89 and Rp-cAMP). IP and preischemic PKA activation substantially reduced infarct size, which was blunted by preischemic PKA inhibition. IP and preischemic PKA activation, but not PKC activation, caused a substantial decrease of Rho-kinase activation during sustained ischemia. These changes were cancelled by preischemic inhibition of PKA but not PKC. Furthermore, either Rho-kinase inhibition (hydroxyfasudil or Y27632) or actin cytoskeletal deactivation (cytochalasin-D) during sustained ischemia achieved the same infarct limitation as preischemic PKA activation without affecting systemic hemodynamic parameters, the area at risk, or collateral blood flow.
  
  
  CONCLUSIONS
  Transient preischemic activation of PKA reduces infarct size through Rho-kinase inhibition and actin cytoskeletal deactivation during sustained ischemia, implicating a novel mechanism for cardioprotection by ischemic preconditioning independent of PKC and a potential new therapeutic target.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Tomi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogai
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Akio
authors.initials: A
authors.lastname: Hirata
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D047908:Intracellular Signaling Peptides and Proteins; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C