Stimulation of α1a Adrenergic Receptors Induces Cellular Proliferation or Antiproliferative Hypertrophy Dependent Solely on Agonist Concentration

Abstract

Stimulation of α1aAdrenergic Receptors (ARs) is known to have anti-proliferative and hypertrophic effects; however, some studies also suggests this receptor can increase cell proliferation. Surprisingly, we find the α1aAR expressed in rat-1 fibroblasts can produce either phenotype, depending exclusively on agonist concentration. Stimulation of the α1aAR by high dose phenylephrine (>10−7 M) induces an antiproliferative, hypertrophic response accompanied by robust and extended p38 activation. Inhibition of p38 with SB203580 prevented the antiproliferative response, while inhibition of Erk or Jnk had no effect. In stark contrast, stimulation of the α1aAR with low dose phenylephrine (∼10−8 M) induced an Erk-dependent increase in cellular proliferation. Agonist-induced Erk phosphorylation was preceded by rapid FGFR and EGFR transactivation; however, only EGFR inhibition blocked Erk activation and proliferation. The general matrix metalloprotease inhibitor, GM6001, blocked agonist induced Erk activation within seconds, strongly suggesting EGFR activation involved extracellular triple membrane pass signaling. Erk activation required little Ca2+ release and was blocked by PLCβ or PKC inhibition but not by intracellular Ca2+ chelation, suggesting Ca2+ independent activation of novel PKC isoforms. In contrast, Ca2+ release was essential for PI3K/Akt activation, which was acutely maximal at non-proliferative doses of agonist. Remarkably, our data suggests EGFR transactivation leading to Erk induced proliferation has the lowest activation threshold of any α1aAR response. The ability of α1aARs to induce proliferation are discussed in light of evidence suggesting antagonistic growth responses reflect native α1aAR function.

Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

“…This observation is consistent with Lei et al who found that PE activates ERK by trans-activating EGFR and FGFR (Epidermal and Fibroblast Growth Factor Receptors) independent of the Ras/Raf/ERK pathway [42], and is also consistent with the data from Duquesnes N et al [15]. However these data contrast with the study of Zou et al[40].…”

“…Figure 8 summarizes the intracellular signaling pathways modulated by Ras in cardiomyocytes. The Ras-independent pathways were suggested by in vitro experiments by Pracyk et al [12] and others[40, 42]. Pressure-overload induces the release of the prohypertrophic ligands endotheline, angiotensin and PE [16].…”

Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses

“…Increased cAMP levels in chondrocytes are associated with a chondrocyte typical phenotype 40 , whereas increased Ca 2þ level are described to induce apoptosis 41 . Also Lei et al 42 described a NE concentration dependent regulation of cell growth with a proliferation decrease after treatment with high doses and a proliferation increase with low doses NE. Taken together with our data we suggest a dual function of the SNS in OA chondrocytes with distinct impact of AR subtypes on metabolic response.…”

Temporal Dissection of Rate Limiting Transcriptional Events Using Pol II ChIP and RNA Analysis of Adrenergic Stress Gene Activation

“…For all studies, an HA-α 1a AR expressing rat-1 cell line was cultured in growth media and treated with 10 −5 M PE to produce the characteristic antiproliferative and hypertrophic response of this receptor [ 37 , 45 , 50 ]. Microarray analysis of α 1a AR-induced gene expression has been reported for rat-1 cells [ 45 ]; however, our analysis of transcriptional activation required detailed temporal information under the specific assay conditions chosen.…”

“…This Gq-activated phospholipase cleaves phosphatidylinositol into the second messengers, diacylglycerol and inositol triphosphate, resulting in acute release of intracellular calcium stores and Protein Kinase C activation. However, a complex array of additional pathways are also activated by the α 1 ARs [ 35 ] including regulation of ion channels [ 36 ] and transactivation of endothelial growth factor receptor [ 37 ]. As part of the fight or flight response [ 38 ], α 1 AR stimulation evokes responses such as vessel contraction within fractions of a second [ 39 ], while other aspects of signaling unfold over minutes (e.g.…”