Novel α₁-Adrenergic Receptor Signaling Pathways: Secreted Factors and Interactions with the Extracellular Matrix

Abstract

␣ 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.

α1-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB

“…Our previous studies used microarray gene expression profiling and real-time RT-PCR and indicated that ␣ 1 -AR activation stimulated dramatic IL-6 mRNA up-regulation in Rat-1 fibroblasts (Gonzalez-Cabrera et al, 2003;Shi et al, 2006). To determine whether our previous observations from Rat-1 fibroblasts were physiologically relevant, we compared our results from Rat-1 fibroblasts with those from primary neonatal CMs throughout this article.…”

“…We have previously demonstrated that activation of ␣ 1 -ARs stimulated IL-6 mRNA expression and protein secretion in Rat-1 fibroblasts stably transfected with any of the three ␣ 1 -AR subtypes (Gonzalez-Cabrera et al, 2003;Shi et al, 2006). In the present study, we have shown for the first time that ␣ 1 -ARs can stimulate IL-6 mRNA expression and protein secretion by regulation of transcription through p38 and NF-B signaling and mRNA stability through yet unknown Signaling pathways involved in ␣ 1 -AR-stimulated IL-6 promoter activity.…”

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…These contradictions are perplexing much as contradictory studies were prior to the delineation of the three α 1 AR subtypes. The answers may lie in the regulators of G-protein signaling (RGS), reactive oxygen species, and cell type-specific downstream effects (Hu et al 1999;Shi et al 2006;Abramow-Newerly et al 2006).…”

Suppression of Collagen Production in Norepinephrine Stimulated Cardiac Fibroblasts Culture: Differential Effect of α and β-Adrenoreceptor Antagonism

“…As carvedilol also exhibits α-blockade activities while doxazosin is an α-blocker, the results suggested that the anti-fibrotic effect of adrenoreceptor blockade is dependent on α-rather than β-blockade. Others also reported that α1 adrenergic receptors were presence in adventitial fibroblasts and a novel signaling pathway related to α1 adrenergic receptors was found to interact with extracellular matrix [30,31].…”