PCPA protects against monocrotaline-induced pulmonary arterial remodeling in rats: potential roles of connective tissue growth factor

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.

Protective Effects of 18β-Glycyrrhetinic Acid on Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

“…Abnormal pulmonary vascular remodeling is considered the primary pathological feature of PAH (Bai et al, 2017), including pulmonary artery wall thickening and pulmonary artery stenosis. These changes can cause vasoconstriction resistance and increased cardiac after-load, eventually leading to PAH.…”

“…Oxidative stress is a critical contributory element in various physiological and pathological processes and in the pathogenesis of PAH caused by MCT (Demarco et al, 2010). The pathological features of PAH mainly include pulmonary vasoconstriction and pulmonary artery wall remodeling (Bai et al, 2017). Oxidative stress has been described in the literature as a pathogenic mechanism of vascular remodeling observed in PAH (Barman et al, 2014).…”

Stimulation of Autophagy by Dapagliflozin Mitigates Cadmium-Induced Testicular Dysfunction in Rats: The Role of AMPK/mTOR and SIRT1/Nrf2/HO-1 Pathways

“…Generally, the pathology of testicular diseases reveals that hyperactive [ 14 ] as well as defective autophagic events [ 12 , 16 ] are described in the literature. In cadmium-induced testicular injury, impaired autophagy flux was detected even in the presence of increased expression of some autophagy signals [ 12 , 16 , 17 ]. In perspective, enhancement of lysosomal membrane permeability [ 18 ] and interference with calcium-dependent autophagosome–lysosome fusion [ 19 ] have been tightly linked to cadmium-evoked autophagy impairment.…”

“…On the other hand, Beclin 1 plays a role in autophagosome production during the autophagic sequestration process. Hence, its levels are decreased in the case of impaired autophagy [ 12 , 16 , 17 ]. Of note, the autophagy events are positively driven by 5’ adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway stimulation, which is brought about by increasing the p-AMPK/total AMPK ratio and lowering the p-mTOR/total mTOR ratio [ 16 , 20 ].…”