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(Circulation Research. 2005;97:574.)
© 2005 American Heart Association, Inc.

Cellular Biology

Cell-Signaling Evidence for Adenosine Stimulation of Coronary Smooth Muscle Proliferation via the A₁ Adenosine Receptor

Jianzhong Shen, Stephen P. Halenda, Michael Sturek, Peter A. Wilden

From the Department of Medical Pharmacology and Physiology (J.S., S.P.H., M.S., P.A.W.), Department of Internal Medicine (M.S.), Center for Diabetes and Cardiovascular Health (J.S., M.S., P.A.W.), University of Missouri-Columbia, School of Medicine; and Department of Cellular and Integrative Physiology (M.S.); Indiana University School of Medicine, Indianapolis.

Correspondence to Peter A. Wilden, PhD, Dept of Medical Pharmacology and Physiology, MA 415, Medical Sciences Bldg, University of Missouri-Columbia, School of Medicine, Columbia, MO 65212. E-mail WildenP{at}health.missouri.edu

For decades, it has been thought that adenosine is exclusively antimitogenic on vascular smooth muscles via the A₂-type adenosine receptor. Recently, we have demonstrated that adenosine stimulates proliferation of porcine coronary artery smooth muscle cells (CASMC) through the A₁ adenosine receptor. However, the cell-signaling mechanisms underlying A₁ receptor–mediated CASMC proliferation in response to adenosine have not been defined. Here, we show that in cultured CASMC, adenosine stimulates phosphorylation of extracellular signal–regulated kinase (ERK), Jun N-terminal kinase (JNK), and AKT in a concentration- and time-dependent manner. This effect is fully mimicked by NECA (nonselective agonist), largely mimicked by CCPA (A₁-selective agonist), weakly mimicked by 2-Cl-IB-MECA (A₃-selective agonist), but not by CGS21680 (A_2A-selective agonist), indicating that adenosine signals strongly via the A₁ receptor to these mitogenic signaling pathways. This interpretation is supported by the finding that adenosine- and CCPA-induced phosphorylation of ERK, JNK, and AKT are inhibited by pertussis toxin (inactivator of Gi proteins) and by DPCPX (A₁-selective antagonist), but not by SCH58261, MRS1706, and VUF5574 (A_2A-, A_2B-, and A₃-selective antagonists, respectively). In addition, adenosine- and CCPA-induced phosphorylation of ERK, JNK, and AKT is inhibited, respectively, by U0126, PD98059 (mitogen-activated protein kinase kinase inhibitors), SP600125 (JNK kinase inhibitor), and wortmannin (phosphatidylinositol 3-kinase inhibitor). Furthermore, these kinase inhibitors abolish or diminish adenosine- and CCPA-induced increases in the rate of cellular DNA synthesis, bromodeoxyuridine incorporation, protein synthesis, and cell number. We conclude that adenosine activates the ERK, JNK, and phosphatidylinositol 3-kinase/AKT pathways primarily through the A₁ receptor, leading to CASMC mitogenesis.

Key Words: porcine • protein kinase • phosphorylation • extracellular signal–regulated kinase • Jun N-terminal kinase • AKT • G protein

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