Icotinib Attenuates Monocrotaline-Induced Pulmonary Hypertension by Preventing Pulmonary Arterial Smooth Muscle Cell Dysfunction

Abstract

Background Aberrant activation of epidermal growth factor receptor (EGFR) signaling pathway is associated with the pathogenesis of pulmonary hypertension (PH). However, the effect of icotinib, a first generation of EGFR tyrosine kinase inhibitor (EGFR-TKI), on PH remains to be elucidated. Methods PH rat model was established by a single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg). Icotinib (15, 30, and 60 mg/kg/day) was administered by oral gavage from the day of MCT injection. After 4 weeks, hemodynamic parameters and histological changes of the pulmonary arterial vessels were assessed, and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) was determined in vivo. Moreover, the effects of icotinib (10 µM) on epidermal growth factor (EGF, 50 ng/ml)-stimulated proliferation, migration, and phenotypic switching of human PASMCs were explored in vitro. Results Icotinib significantly reduced the right ventricular systolic pressure and right ventricle hypertrophy index in rats with MCT-induced PH. Moreover, icotinib improved MCT-induced pulmonary vascular remodeling. The expression of contractile marker (smooth muscle 22 alpha (SM22α)) and synthetic markers (osteopontin (OPN) and vimentin) in pulmonary artery was restored by icotinib treatment. In vitro, icotinib suppressed EGF-induced PASMCs proliferation and migration. Meanwhile, icotinib inhibited EGF-induced downregulation of α-smooth muscle actin and SM22α and upregulation of OPN and Collagen I in PASMCs, suggesting that icotinib could inhibit EGF-induced phenotypic switching of PASMCs. Mechanistically, these effects of icotinib were associated with the inhibition of EGFR-Akt/ERK signaling pathway. Conclusions Icotinib can attenuate MCT-induced pulmonary vascular remodeling and improve PH. This effect of icotinib might be attributed to preventing PASMC dysfunction by inhibiting EGFR-Akt/ERK signaling pathway.

The zinc transporter ZIP12 regulates monocrotaline-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/ERK signaling pathways

“…To some extent, the biological patterns involved in PAH share several features with cancer, including unrestrained cell proliferation, enhanced migration, and resistance to apoptosis [ 40 ]. High proliferation and migration of PASMCs have been associated with the PI3K/AKT and ERK signaling pathways [ 41 – 45 ]. PI3K is a cytoplasmic lipid kinase involved in the regulation of a variety of processes that are critical for cell survival.…”

Inhibition of Bruton’s Tyrosine Kinase Alleviates Monocrotaline-Induced Pulmonary Arterial Hypertension by Modulating Macrophage Polarization

“…The reactions were visualized using diaminobenzidine chromogenic solution. The degree of muscularization was defined by the proportion of α -SMA-positive parts of circumference according to a previous study [ 19 ]. The muscularization of distal vessels with diameter 25–100 μ m was quantified, and the percentages of nonmuscularized, partially muscularized, and fully muscularized vessels were calculated.…”

EGFR-TKIs - induced cardiotoxicity in NSCLC: incidence, evaluation, and monitoring

“…It is worth noting that Peng et al. ( 23 ) reported that icotinib can significantly reduce the right ventricular systolic blood pressure and right ventricular hypertrophy index of cytroline-induced pulmonary hypertension in rats, and improve the pulmonary vascular remodeling induced by monocrotaline, and proposed that this effect may prevent the dysfunction of pulmonary artery smooth muscle cells by inhibiting the EGFR-Akt/ERK signaling pathway.…”