Novel alpha1-adrenergic receptor signaling pathways: secreted factors and interactions with the extracellular matrix.
alpha1-Adrenergic receptor (alpha1-ARs) subtypes (alpha1A, alpha1B, and alpha1D) 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 alpha1A-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 alpha1A-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 alpha1A-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 alpha1-ARs induced adhesion in three cell types to vitronectin, an interaction that was also integrin-, FGF7-, and PKC-dependent. alpha1-AR activation also inhibited cell migration, which was integrin- and PKC-independent but still required secretion of FGF7. alpha1-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 alpha1-ARs may be involved in proinflammatory responses. Our results indicate alpha1-ARs induce the secretion of factors that interact with the extracellular matrix to regulate cell adhesion, motility and proinflammatory responses through novel signaling pathways.
Shi
Ting
T
Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Duan
Zhong-Hui
ZH
Papay
Robert
R
Pluskota
Elzbieta
E
Gaivin
Robert J
RJ
de la Motte
Carol A
CA
Plow
Edward F
EF
Perez
Dianne M
DM
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010617:Phenanthridines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000470:Alkaloids; D053119:Benzophenanthridines; D016326:Extracellular Matrix Proteins; C496455:Fgf7 protein, rat; D015850:Interleukin-6; D010617:Phenanthridines; D018340:Receptors, Adrenergic, alpha-1; D019096:Vitronectin; D051523:Fibroblast Growth Factor 7; C016299:chelerythrine; D011493:Protein Kinase C; D011224:Prazosin