Published online before print January 29, 2004, doi: 10.1161/01.RES.0000119169.87429.A0
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins
From the Institut für Pharmakologie und Klinische Pharmakologie (M. Sussmann, J.M.-K., K.S., J.W.F.), Heinrich Heine Universität Düsseldorf; Institut für Allgemeine Pathologie der Technischen Universität München (M. Sarbia), München; Klinik für Allgemeine Kinderheilkunde (R.M.N.), Phillips Universität, Marburg, Germany.
Correspondence to Jens W. Fischer, Molecular Pharmacology, Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail jens.fischer{at}uni-duesseldorf.de
Hyaluronic acid (HA) is a prominent constituent of the extracellular matrix of atherosclerotic vascular lesions in humans known to modulate vascular smooth muscle phenotype. The regulation of HA synthesis by vasodilatory prostaglandins was analyzed in human arterial smooth muscle cells (SMCs). The prostacyclin analogue, iloprost (100 nmol/L), markedly increased pericellular formation of HA coats and HA secretion into the cell culture medium in human arterial SMCs (8.7±1.6-fold). Expression of HA synthase 2 (HAS2) was determined by semiquantitative RT-PCR and found to be strongly upregulated at concentrations of iloprost between 1 and 100 nmol/L after 3 hours. Furthermore, endogenous cyclooxygenase-2 (COX2) activity was required for basal expression of HAS2 mRNA in SMCs in vitro. Total HA secretion in response to iloprost was markedly decreased by RNA interference (RNAi), specific for HAS2. In addition, siRNA targeting HAS2 strongly increased the spreading of human SMCs compared with mock-transfected cells. HAS2 mRNA levels were also stimulated by a selective prostacyclin receptor (IP) agonist, cicaprost (10 nmol/L), prostaglandin E2 (10 nmol/L), and the EP2 receptor agonist, butaprost (1 µmol/L). Induction of HAS2 mRNA and HA synthesis by prostaglandins was mimicked by stable cAMP analogues and forskolin. In human atherectomy specimens from the internal carotid artery, HA deposits and COX2 expression colocalized frequently. In addition, strong EP2 receptor expression was detected in SMCs in HA-rich areas. Therefore, upregulation of HAS2 expression via EP2 and IP receptors might contribute to the accumulation of HA during human atherosclerosis, thereby mediating proatherosclerotic functions of COX2.
Key Words: hyaluronic acid • extracellular matrix • prostaglandins • cyclooxygenase-2 • atherosclerosis
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