© 2000 American Heart Association, Inc.
Vascular Biology |
Cytokines Induce Upregulation of Vascular P2Y2 Receptors and Increased Mitogenic Responses to UTP and ATP
From the Division of Experimental Vascular Research, Department of Medicine, Lund University Hospital, Lund, Sweden.
Correspondence to Dr David Erlinge, Department of Cardiology, Lund University Hospital, S-221 85 Lund, Sweden. E-mail david.erlinge{at}med.lu.se
Abstract—P2Y2
receptors, which mediate contractile and mitogenic effects
of extracellular nucleotides in vascular smooth muscle
cells (VSMCs), are upregulated in the synthetic phenotype of
VSMCs and in the neointima after balloon angioplasty,
suggesting a role in the development of
atherosclerosis. Because released cytokines in
atherosclerotic lesions mediate multiple effects on gene transcription
in VSMCs, we speculated that cytokines could be involved in the
regulation of P2Y2 receptor expression. Using a competitive
reverse transcription–polymerase chain reaction, we detected that
interleukin (IL)-1ß induced a time- and dose-dependent upregulation
of P2Y2 receptor mRNA, which was dramatically enhanced when
combined with interferon-
or tumor necrosis factor-
.
Lipopolysaccharide also significantly increased the expression
of P2Y2 receptor mRNA. The upregulation of P2Y2
receptor mRNA was paralleled at the functional level because
IL-1ß significantly increased the UTP-stimulated DNA synthesis and
the release of intracellular Ca2+. Actinomycin D completely
blocked the upregulation of P2Y2 receptor mRNA expression
by IL-1ß, indicating de novo mRNA synthesis. There was no cAMP
accumulation in the cells stimulated with IL-1ß. The
cyclooxygenase inhibitor
indomethacin and the protein kinase C
inhibitor RO-31-8220 inhibited IL-1ß–induced
upregulation of P2Y2 receptor mRNA expression, whereas
rapamycin and PD098059 had no effects. Furthermore, neither P38
mitogen-activated protein kinase inhibitor SB20358
alone nor its combination with PD098059 blocked the effect of IL-1ß
on the expression of P2Y2 receptor mRNA. Our results
demonstrate that inflammatory mediators upregulate vascular
P2Y2 receptors at the transcriptional and at the functional
level through protein kinase C and cyclooxygenase
but not cAMP, extracellular signal–regulated kinases 1 and 2, or
P38-dependent pathways. This may result in increased growth-stimulatory
or contractile effects of extracellular UTP and ATP, which may be of
importance in the development of vascular disease.
Key Words: P2Y2 receptors • interleukin-1ß • competitive reverse transcription–polymerase chain reaction
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