Dacomitinib, a new pan-EGFR inhibitor, is effective in attenuating pulmonary vascular remodeling and pulmonary hypertension.

Accumulating evidence suggests that epidermal growth factor receptor (EGFR) plays a role in the progression of pulmonary arterial hypertension (PAH). Clinically-approved epidermal growth factor inhibitors such as gefitinib, erlotinib, and lapatinib have been explored for PAH. However, None of them were able to attenuate PAH. So, we explored the role of dacomitinib, a new pan-EGFR inhibitor, in PAH. Adult male Sprague-Dawley rats were used to study hypoxia- or monocrotaline-induced right ventricular remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and pressure-volume vessels were performed. Immunohistochemical staining, flow cytometry, and viability, as well as scratch-wound, and Boyden chamber migration assays were used to identify the roles of dacomitinib in pulmonary artery smooth muscle cells (PASMCs). The results revealed that dacomitinib has a significant inhibitory effect on the thickening of the media, adventitial collagen increased. Dacomitinib also has a significant role in attenuating pulmonary artery pressure and right ventricular hypertrophy. Additionally, dacomitinib inhibits hypoxia-induced proliferation, migration, autophagy and cell cycle progression through PI3K-AKT-mTOR signaling in PASMCs. Our study indicates that dacomitinib inhibited hypoxia-induced cell cycle progression, proliferation, migration, and autophagy of PASMCs, thereby attenuating pulmonary vascular remodeling and development of PAH via the PI3K-AKT-mTOR signaling pathway. Overall, dacomitinib may serve as new potential therapeutic for the treatment of PAH.

Yu X ，Zhao X ，Zhang J ，Li Y ，Sheng P ，Ma C ，Zhang L ，Hao X ，Zheng X ，Xing Y ，Qiao H ，Qu L ，Zhu D ... -  《-》

Protective effects of dioscin on vascular remodeling in pulmonary arterial hypertension via adjusting GRB2/ERK/PI3K-AKT signal.

Pulmonary arterial hypertension (PAH) is a progressive and lethal cardiopulmonary. Pulmonary vascular remodeling (PVR) caused by excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) is the chief pathological feature of PAH. Dioscin is a natural product that possesses multiple pharmacological activities, but its effect on PAH remains unclear. In this study, effect of dioscin on vascular remodeling in PAH was assessed in hypoxia-induced PASMCs, hypoxia-induced and monocrotaline (MCT)-induced rats. Western blot, Real-time PCR and siRNA transfection tests were applied to evaluate the possible mechanisms of dioscin. In vitro experiments, results showed dioscin markedly inhibited the proliferation and migration, and promoted apoptosis of hypoxic PASMCs. In vivo, dioscin significantly decreased the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI), and improved pulmonary vascular stenosis in rats induced by hypoxia or MCT. Molecular mechanism studies showed that dioscin significantly reduced the expression of growth factor receptor-bound protein 2 (GRB2). Subsequently, dioscin reduced the expressions of Ras, Cyclin D1, CDK4, c-Fos, PCNA and p-ERK to inhibit proliferation and migration of PASMCs, inhibited p-PI3K and p-AKT levels and increased Bax/Bcl2 ratio to promote cell apoptosis. GRB2 siRNA transfection in PASMCs further confirmed that the inhibitory action of dioscin in PAH was evoked by adjusting GRB2/ERK/PI3K-AKT signal. Taken together, our study indicated that dioscin attenuates PAH through adjusting GRB2/ERK/PI3K-AKT signal to inhibit PASMCs proliferation and migration, and promote apoptosis, and dioscin may be developed as a therapeutic strategy for treating PAH in the future.

Yang Y ，Yin L ，Zhu M ，Song S ，Sun C ，Han X ，Xu Y ，Zhao Y ，Qi Y ，Xu L ，Peng JY ... -  《-》

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

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. 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. 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. 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.

Peng LY ，Yu M ，Yang MX ，Liu P ，Zhou H ，Huang W ，Kong H ，Xie WP ... -  《-》

A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension.

Wang AP ，Li XH ，Yang YM ，Li WQ ，Zhang W ，Hu CP ，Zhang Z ，Li YJ ... -  《PLoS One》

Inhibition of Src activation reverses pulmonary vascular remodeling in experimental pulmonary arterial hypertension via Akt/mTOR/HIF-1<alpha> signaling pathway.

Pulmonary arterial hypertension (PAH) is a diffuse pulmonary microvascular remodeling disease accompanied by malignant proliferation of pulmonary artery smooth muscle cells (PASMCs), which causes persistent pulmonary artery pressure elevation, right ventricular hypertrophy (RVH) and death. However, current therapies targeting pulmonary vascular remodeling and RVH remain poorly effective in reversing PAH. Overactivation of the protein tyrosine kinase Src plays an important role in tumor cell growth, proliferation and invasion; we thus hypothesized that inhibitors targeting Src activation could reverse experimental PAH. We demonstrated that Src was markedly activated in hypoxia-stimulated PASMCs from donors and PASMCs isolated from PAH patients. We investigated the effects of the Src-selective inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) and berberine (BBR) on PAH-PASMC proliferation and migration by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) and wound-healing assays. Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression through Akt/mTOR signal pathway. In vivo, PP1 and BBR significantly alleviated distal pulmonary vascular remodeling and decreased right ventricular systolic pressure (RVSP) and RVH in Sugen (SU) 5416/hypoxia (SU-PAH) mice. These findings demonstrate that pharmacological (PP1 or BBR) inhibition of Src activation could be a novel means of treating severe pulmonary vascular remodeling and RVH in PAH patients.

Liu P ，Gu Y ，Luo J ，Ye P ，Zheng Y ，Yu W ，Chen S ... -  《-》