on June 21, 2004
Published online before print June 21, 2004, doi: 10.1161/01.CIR.0000133390.12306.C7
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Submitted on November 15, 2003
From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita; Cardiovascular Division (K.N.), Department of Medicine, Saga University Faculty of Medicine, Saga; Cardiovascular Division of Medicine (A.O., H.T., M.K.), National Cardiovascular Center, Suita; Department of Physiological Science (Y.S.), Tokai University School of Medicine, Isehara; and Department of Cardiovascular Medicine (H.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. * To whom correspondence should be addressed. E-mail: kitakaze{at}zf6.so-net.ne.jp.
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. Methods and 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.
Revised on March 10, 2004
Accepted on March 17, 2004
Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C
Shoji Sanada MD, PhD,
Key words: ischemia • infarction • proteins
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