Published online before print June 21, 2004, doi: 10.1161/01.CIR.0000133390.12306.C7
(Circulation. 2004;110:51-57.)
© 2004 American Heart Association, Inc.
Original Articles |
Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C
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.
Correspondence to Masafumi Kitakaze, MD, PhD, Cardiovascular Division of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, 565-8565 Japan. E-mail kitakaze{at}zf6.so-net.ne.jp
Received November 15, 2003; de novo received December 28, 2003; revision received March 10, 2004; accepted March 17, 2004.
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.
Key Words: ischemia • infarction • proteins
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