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(Circulation Research. 2005;96:982.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Novel Mitogenic Effect of Adenosine on Coronary Artery Smooth Muscle Cells

Role for 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.H., M.S., P.W.), Department of Internal Medicine (M.S.), Center for Diabetes and Cardiovascular Health (J.S., M.S., P.W.), University of Missouri-Columbia, School of Medicine, Columbia, Mo; and Department of Cellular and Integrative Physiology (M.S.), Indiana University School of Medicine, Indianapolis, Ind.

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

Adenosine is a vascular endothelial cell mitogen, but anti-mitogenic for aortic smooth muscle cells and fibroblasts when acting via the A_2B adenosine receptor. However, we show that adenosine increases porcine coronary artery smooth muscle cell (CASMC) number, cellular DNA content, protein synthesis, and PCNA staining. RT-PCR analysis indicates that porcine CASMC express A₁, A_2A, A₃, and barely detectable levels of A_2B receptor mRNAs. The mitogenic effect of adenosine is mimicked by NECA, CCPA, and R-PIA, but not by CGS21680and 2-Cl-IB-MECA, and is inhibited by DPCPX, indicating a prominent role for the A₁ receptor. This interpretation is supported by the finding that adenosine- and CCPA-induced DNA synthesis is significantly inhibited by pertussis toxin, but substantially potentiated by PD81723, an allosteric enhancer of the A₁ receptor. When a cDNA encoding the porcine A₁ receptor was cloned and expressed in COS-1 cells, A₁ receptor pharmacology is confirmed. Anti-sense oligonucleotides to the cloned sequence dramatically suppress the mitogenic effect of adenosine and CCPA. Conversely, over-expression of the cloned A₁ receptor in CASMC increases adenosine- and CCPA-induced DNA synthesis. Furthermore, stimulation with adenosine or CCPA of intact coronary arteries in an organ culture model of vascular disease increases cellular DNA synthesis, which was abolished by DPCPX. We conclude that adenosine acts as a novel mitogen in porcine CASMC that express the A₁ adenosine receptor, possibly contributing to the development of coronary artery disease.

Key Words: adenosine receptors • coronary artery smooth muscle cells • proliferation • molecular cloning • porcine

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