Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells

Abstract

Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10(-11)-10(-7) M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ET(A) and ET(B) receptors, cell size, as well as increased expression of myosin heavy chain, alpha-smooth muscle actin, and calponin. ET-1-induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK1/2 by the MAPK/ERK kinase 1/2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M and greater than that induced by cardiotrophin-1. ET-1 induced release of IL-6 but not IL-11, leukemia inhibitory factor, oncostatin M, or cardiotrophin-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.

Thymic Stromal Lymphopoietin Receptor-Mediated IL-6 and CC/CXC Chemokines Expression in Human Airway Smooth Muscle Cells: Role of MAPKs (ERK1/2, p38, and JNK) and STAT3 Pathways

“…It is well known that MAPK (at least ERK1/2) can modulate the STAT3 activation in HASM (22,55) and HEK293 cell line (56). In particular, TSLP-induced IL-8/CXCL expression in our study may be explained by a study in dermal fibroblasts where thrombin activated ERK1/2, p38MAPK, and STAT3 to induce IL-8/CXCL8 release (57).…”

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…A subsequent study revealed that endothelin-1, which is elevated in asthmatic airways [97], may also promote increased ASM mass via its effects on cell growth and apoptosis [98]. Indeed, endothelin-1 markedly reduced the apoptosis of human ASM cells induced by serum withdrawal, and, in combination with cardiotrophin-1, further promoted ASM hypertrophy and accumulation of contractile apparatusassociated proteins [96,98]. FREYER et al [99] reported that ECM components, such as fibronectin, laminin-1 and collagens I and IV, provide strong survival signals to cultured human ASM cells, an effect that is mediated, in part, via integrin a5b1.…”

“…Notably, cardiotrophin-1, a member of the gp130/IL-6 cytokine family that is synthesised by ASM cells, inhibits, via p42/ p44 mitogen-activated protein kinase (MAPK), human ASM cell apoptosis induced by serum deprivation or FasL/TNF-a exposure [96]. A subsequent study revealed that endothelin-1, which is elevated in asthmatic airways [97], may also promote increased ASM mass via its effects on cell growth and apoptosis [98]. Indeed, endothelin-1 markedly reduced the apoptosis of human ASM cells induced by serum withdrawal, and, in combination with cardiotrophin-1, further promoted ASM hypertrophy and accumulation of contractile apparatusassociated proteins [96,98].…”

The H3K4me3 Histone Demethylase Fbxl10 Is a Regulator of Chemokine Expression, Cellular Morphology, and the Metabolome of Fibroblasts

“…5A we could show here that Fbxl10 regulates the expression of genes encoding cell adhesion molecules and extracellular matrix proteins including Col2A1 and Lama5. Further genes of this cluster like Efnb2 and Efna5 were previously described to alter cell morphology whereas Edn1 is known to influence cell size and is involved in cellular hypertrophy (27)(28)(29). These genes are of special interest regarding the altered morphology of D5 compared with the control cell line (supplemental Fig.…”