Abstract
The purpose of this study was to investigate the mechanism of monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and determine whether 4-chloro-DL-phenylalanine (PCPA) could inhibit pulmonary arterial remodeling associated with connective tissue growth factor (CTGF) expression and downstream signal pathway. MCT was administered to forty Sprague Dawley rats to establish the PAH model. PCPA was administered at doses of 50 and 100 mg/kg once daily for 3 weeks via intraperitoneal injection. On day 22, the pulmonary arterial pressure (PAP), right ventricle hypertrophy index (RVI) and pulmonary artery morphology were assessed and the serotonin receptor-1B (SR-1B), CTGF, p-ERK/ERK were measured by western blot or immunohistochemistry. The concentration of serotonin in plasma was checked by ELISA. Apoptosis and apoptosis-related indexes were detected by TUNEL and western blot. In the MCT-induced PAH models, the PAP, RVI, pulmonary vascular remodeling, SR-1B index, CTGF index, anti-apoptotic factors bcl-xl and bcl-2, serotonin concentration in plasma were all increased and the pro-apoptotic factor caspase-3 was reduced. PCPA significantly ameliorated pulmonary arterial remodeling induced by MCT, and this action was associated with accelerated apoptosis and down-regulation of CTGF, SR-1B and p-ERK/ERK. The present study suggests that PCPA protects against the pathogenesis of PAH by suppressing remodeling and inducing apoptosis, which are likely associated with CTGF and downstream ERK signaling pathway in rats.
Highlights
Pulmonary artery hypertension (PAH) is a progressive and devastating disease defined by increased pulmonary arterial pressure (>25 mmHg), vascular remodeling and narrowed pulmonary arteries [1, 2]
We showed that PCPA can ameliorate MCT-induced pulmonary artery hypertension (PAH) which might associate with downregulated serotonin receptor-1B (SR-1B), connective tissue growth factor (CTGF) and its downstream signaling pathway
Our results indicated that the expression of 5-HT, SR-1B, CTGF, p-extracellular signal-regulated kinase (ERK)/ERK, bcl-2 and bcl-xl is significantly increased and the expression of caspase-3 is www.impactjournals.com/oncotarget decreased in the MCT group
Summary
Pulmonary artery hypertension (PAH) is a progressive and devastating disease defined by increased pulmonary arterial pressure (>25 mmHg), vascular remodeling and narrowed pulmonary arteries [1, 2]. Endothelial cell injury and apoptosis are generally considered to represent PAH initiation and they are caused by several factors which can induce pulmonary arterial smooth muscle cells (PASMCs) and fibroblast proliferation as well as vascular remodeling [8,9,10]. Programmed cell death, is an automatic and ordered cell death process that is controlled by several genes which maintains homeostasis [11]. In this process, damaged cells or unwanted cells that might be disadvantageous to the organism are removed [11]. Agents designed to induce apoptosis or inhibit PASMCs growth represent effective and promising approaches
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