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Novel ₁-Adrenergic Receptor Signaling Pathways: Secreted Factors and Interactions with the Extracellular Matrix

Departments of Molecular Cardiology (T.S., R.P., E.P., R.J.G., E.F.P., D.M.P.) and Pathobiology (C.A.d.l.M.), the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, Ohio; and Department of Computer Science, University of Akron, Akron, Ohio (Z.-H.D.)

₁-Adrenergic receptor (₁-ARs) subtypes (_1A, _1B, and _1D) regulate multiple signal pathways, such as phospholipase C, protein kinase C (PKC), and mitogen-activated protein kinases. We employed oligonucleotide microarray technology to explore the effects of both short- (1 h) and long-term (18 h) activation of the _1A-AR to enable RNA changes to occur downstream of earlier well characterized signaling pathways, promoting novel couplings. Polymerase chain reaction (PCR) studies confirmed that PKC was a critical regulator of _1A-AR-mediated gene expression, and secreted interleukin (IL)-6 also contributed to gene expression alterations. We next focused on two novel signaling pathways that might be mediated through _1A-AR stimulation because of the clustering of gene expression changes for cell adhesion/motility (syndecan-4 and tenascin-C) and hyaluronan (HA) signaling. We confirmed that ₁-ARs induced adhesion in three cell types to vitronectin, an interaction that was also integrin-, FGF7-, and PKC-dependent. ₁-AR activation also inhibited cell migration, which was integrin- and PKC-independent but still required secretion of FGF7. ₁-AR activation also increased the expression and deposition of HA, a glycosaminoglycan, which displayed two distinct structures: pericellular coats and long cable structures, as well as increasing expression of the HA receptor, CD44. Long cable structures of HA can bind leukocytes, which this suggests that ₁-ARs may be involved in proinflammatory responses. Our results indicate ₁-ARs induce the secretion of factors that interact with the extracellular matrix to regulate cell adhesion, motility and proinflammatory responses through novel signaling pathways.

Address correspondence to: Dianne M. Perez, Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: perezd{at}ccf.org

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