ERK1/2 Signaling Pathway Modulates the Airway Smooth Muscle Cell Phenotype in the Rat Model of Chronic Asthma

Abstract

Background: It has been demonstrated that the phenotypic modulation of airway smooth muscle cells (ASMCs) is important to the pathogenesis of airway remodeling in chronic asthma. The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is one of the most important transduction pathways involved in the process of asthma; however, its role in the phenotypic transition of ASMCs remains unclear. Objectives: To examine the role of ERK1/2 in the phenotypic modulation of ASMCs in the rat model of chronic asthma. Methods: Bronchial smooth muscle strips were cultured in vitro in the presence of the ERK1/2 agonist epidermal growth factor or/and the MEK inhibitor PD98059. The phenotype of ASMCs was determined by observing these cells under an electron microscope and analyzing expression of phenotypic markers (smooth muscle α-actin for the contractile phenotype and osteopontin for the synthetic) by using Western blot and reverse-transcriptase polymerase chain reaction, respectively. Results: The phenotype of the ASMCs from the chronic asthmatic rats changed from the contractile type to the synthetic type with synthetic organelles abundantly gathered around the nucleus and altered expression of phenotypic markers. ERK1/2 was strongly expressed in the ASMCs of the chronic asthmatic rats and its activation by epidermal growth factor excessively promoted the synthetic function of ASMCs; the MEK inhibitor PD98059, however, reversed this phenotypic change in the ASMCs. Conclusions: Our results reveal a key role of the ERK1/2 signaling pathway in the phenotypic modulation of ASMCs in chronic asthmatic rats, indicating that specific inhibition of ERK1/2 in ASMCs may be therapeutically valuable in the control of airway remodeling in chronic asthma.

Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway

“…42,43 Activation of ERK can promote the phosphorylation of cytosolic target proteins or regulate the activity of other protein kinases, promoting phosphorylation of multiple transcription factors and enhancing transcriptional activity. 44,45 In the present study, pravastatin significantly inhibited the increase in p-ERK1/2 expression in aortas from apoE −/− mice.…”

“…Many studies have demonstrated that in some cardiovascular diseases, such as atherosclerosis, ERK1/2 induces the phenotypic modulation of vascular cells during the progression of vessel remodelling . Activation of ERK can promote the phosphorylation of cytosolic target proteins or regulate the activity of other protein kinases, promoting phosphorylation of multiple transcription factors and enhancing transcriptional activity . In the present study, pravastatin significantly inhibited the increase in p‐ERK1/2 expression in aortas from apoE −/− mice.…”

Tetramethylpyrazine Protects Bone Marrow-Derived Mesenchymal Stem Cells against Hydrogen Peroxide-Induced Apoptosis through PI3K/Akt and ERK1/2 Pathways

“…29) Phosphorylated ERK1/2 moves from the cytoplasm across the nuclear membrane, activates associated proteins, induces Bcl-2-associated death promoter (BAD) phosphorylation, and activates a variety of nuclear transcription factors to play a role in anti-apoptosis. 30,31) In our experiments, TMP pretreatment increased the expression levels of p-Akt and p-ERK1/2 in H 2 O 2 -treated BMSCs. We speculated that TMP could modulate the activity of p-Akt and p-ERK1/2 to adjust the expression of apoptosis-related proteins.…”

Small interfering RNA against ERK1/2 attenuates cigarette smoke‑induced pulmonary vascular remodeling

“…Previous results have revealed that cigarette smoke exerts its biological effects via the ERK1/2 signaling pathway ( 8 ). Moreover, a critical role for ERK1/2 activation in the abnormal proliferation of vascular smooth muscle cells and airway smooth muscle cells has been suggested during vessel remodeling ( 11 – 14 ). The present study extended this finding and demonstrated that the expression of p-ERK1/2 was upregulated by CSE stimulation, indicating that activated ERK1/2 is involved in the CSE-induced proliferation of primary rPASMCs.…”

“…Activation of ERK1/2 (p-ERK1/2) has been implicated as a regulator in numerous fundamental cellular activities ( 9 , 10 ). Studies by the current authors and other researchers have addressed the role of the ERK1/2 signaling pathway in the proliferation of airway smooth muscle cells and multiple arterial smooth muscle cells ( 11 – 14 ).…”