Published online before print March 18, 2004, doi: 10.1161/01.RES.0000126048.32383.6B
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Submitted on June 19, 2003
Revised on March 8, 2004
Accepted on March 9, 2004
G Protein-Coupled Receptor Internalization Signaling Is Required for Cardioprotection in Ischemic Preconditioning
Haiyan Tong ;
From the Laboratory of Signal Transduction (H.T., E.M.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, and Department of Medicine, Cell Biology and Genetics (H.A.R.), Department of Surgery (W.J.K.), and Department of Pathology (H.T., C.S.), Duke University Medical Center, Durham, NC. W.J.K. is presently at the Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa.
* To whom correspondence should be addressed. E-mail: murphy1{at}niehs.nih.gov.
The present study is designed to explore the role of G protein-coupled receptors (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG mice with cardiac-specific overexpression of a G
-sequestering peptide, ARKct (TG ARKct mice), to test whether the protection of PC is G-dependent. To test the role of Gi protein, we used wild-type mice pretreated with the Gi inhibitor pertussis toxin. Recovery of left ventricular developed pressure and infarct size were measured as indices of protection. PC induced protection in wild-type mice, but this protection was blocked by pertussis toxin treatment and was also blocked in TG ARKct mice. To determine the mechanism of G-induced protection in PC, we investigated one of the downstream targets of G, the PI3K/p70S6K pathway. PC-induced phosphorylation of p70S6K was not blocked in TG ARKct hearts; therefore, we investigated other targets of G. Recent studies suggest a role for G in GPCR internalization. We found that ARKct, a specific PI3K inhibitor wortmannin, and bafilomycin A1, which all block receptor recycling, all blocked the protective effect of PC. To additionally test whether PI3K is involved in PC-activated receptor internalization and endosomal signaling, we used TG mice with cardiac-specific overexpression of a catalytically inactive mutant PI3K, which disrupts the recruitment of functional PI3K to agonist-activated GPCRs in vivo. We found that the catalytically inactive mutant of PI3K blocks the protection of PC. In summary, these data suggest the novel finding that the cardioprotective effect of PC requires receptor internalization.
Key words: G
•
phosphatidylinositol 3-kinase •
transgenic mice •
isolated heart •
ischemic preconditioning
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