Journal
CIRCULATION RESEARCH
Volume 97, Issue 6, Pages 574-582Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000181159.83588.4b
Keywords
porcine; protein kinase; phosphorylation; extracellular signal; regulated kinase; Jun N-terminal kinase; AKT; G protein
Funding
- NCRR NIH HHS [RR13223] Funding Source: Medline
- NHLBI NIH HHS [HL62552] Funding Source: Medline
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For decades, it has been thought that adenosine is exclusively antimitogenic on vascular smooth muscles via the A(2)-type adenosine receptor. Recently, we have demonstrated that adenosine stimulates proliferation of porcine coronary artery smooth muscle cells (CASMC) through the A(1) adenosine receptor. However, the cell-signaling mechanisms underlying A(1) 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 (NK), and AKT in a concentration-and time-dependent manner. This effect is fully mimicked by NECA (nonselective agonist), largely mimicked by CCPA (A(1)-selective agonist), weakly mimicked by 2-Cl-IB-MECA (A(3)-selective agonist), but not by CGS21680 (A(2A)-selective agonist), indicating that adenosine signals strongly via the A(1) 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 G(i) proteins) and by DPCPX (A(1)-selective antagonist), but not by SCH58261, MRS1706, and VUF5574 (A(2A)-, A(2B)-, and A(3)-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 A(1) receptor, leading to CASMC mitogenesis.
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