Endothelin-1 Regulates Proliferative Responses, both alone and Synergistically with PDGF, in Rat Tracheal Smooth Muscle Cells

Abstract

The peptide, endothelin-1 (ET-1) regulates proliferative responses in numerous cell types. Recently, a dual ET receptor antagonist was shown to prevent the increase in airway smooth muscle cell (SMC) proliferation that accompanies airway smooth muscle remodeling in a rat model of experimental asthma. Thus, we used [3H]-thymidine incorporation assays and western immunoblotting to identify signaling pathways that regulate proliferative responses in cultured rat tracheal SMC. Our data indicate that ET-1 activation of the ET A receptor subtype induced [3H]-thymidine incorporation and activation of ERK 1/2 in primary rat tracheal SMC. ET-1-induced [3H]-thymidine incorporation and activation of ERK 1/2 were inhibited by pretreatment of SMC with pertussis toxin or down regulation of phorbol ester responsive isoforms of PKC. While ET- 1-induced ERK 1/2 activation was unaffected following inhibition of Rho kinase, ET-1-induced [3H]-thymidine incorporation was abrogated. ET-1 also potentiated [3H]-thymidine incorporation as well as cell proliferation of SMC stimulated with PDGF-BB and this response did not appear to be regulated by ERK1/ 2. These data demonstrate that ET-1 induces activation of multiple G proteins that regulate rat tracheal SMC proliferative responses, likely through signaling pathways downstream of ERK1/2 and Rho kinase.

Leukotriene D4‐induced, epithelial cell‐derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation

“…Endothelin-1, for example, is produced mainly by the epithelium, and has been shown to be overexpressed in the airways of asthmatics [57,58]. Interestingly, this GPCR ligand also supports BSMC proliferation alone or in combination with growth factor [59,60]. However, the effect of endothelin-1 in the increased mass of BSMC observed in asthmatics may also be related to its hypertrophic and/or its anti-apoptotic effects [61].…”

Rho-associated coiled-coil containing kinases (ROCK)

“…In accordance with this, ROCK inhibitors have been shown to have antiproliferative effects in some cell types including airway and prostatic smooth muscle cells and cardiac myocytes. 94,111,112 Conversely, active ROCK can induce proliferation in some cell types including fibroblasts, in which modulation of the levels of specific cell cycle regulators appears to play an important role. 113 The influence of ROCK activity on the levels of cell cycle regulatory proteins also has been implicated in the proliferation of corneal epithelial cells 114 and gastric cells.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…(PDGF)-BB is a potent stimulator of airway smooth muscle proliferation (Hirst et al, 1996) and may act synergistically with other growth factors such as endothelin-1 (Yahiaoui et al, 2006). The proliferative effect of PDGF is mediated via activation of STAT-3 and the small GTPase Rac-1 (Simeone-Penney et al, 2008).…”