Expression of peptide fragments from proADM and involvement of mitogen‐activated protein kinase signaling pathways in pulmonary remodeling induced by high pulmonary blood flow

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary arterial remodeling and right ventricular failure. Despite recent advances in pathophysiological mechanism exploration and new therapeutic approaches, PAH remains a challenging condition. In this study, we investigated the roles of the peptide fragments from proadrenomedullin (proADM) such as adrenomedullin (ADM), adrenotensin (ADT), and proadrenomedullin N-terminal 20 peptide (PAMP) during pulmonary remodeling caused by high pulmonary blood flow, and probed the possible involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways. Sixteen rat models of PAH were artificially established by surgically connecting the left common carotid artery to the external jugular vein. We subcutaneously injected an extracellular signal-regulated protein kinase (ERK1/2) inhibitor, PD98059, in eight rats, treated another eight rats with an equal volume of saline. Eight rats without connections served as the control group. We observed that mRNA expression levels of ADM, stress-activated protein kinase (SAPK), and ERK1/2 were significantly elevated in the shunted rats; furthermore, ERK1/2 levels were significantly inhibited by PD98059. Protein levels of ADM, PAMP, p-SAPK, and p-ERK1/2 were significantly higher ADT was lower, and p-p38 remained unchanged in the rat models compared with the controls. However, the protein expression of both ADM and p-ERK1/2 was significantly inhibited by PD98059. Our results suggest that levels of ADM, ADT, and PAMP respond to pulmonary remodeling, and that activation of the SAPK and ERK1/2 signaling pathways is involved in pulmonary hypertension and artery remodeling caused by high pulmonary blood flow.

Chronic obstructive sleep apnea accelerates pulmonary remodeling via TGF-β/miR-185/CoLA1 signaling in a canine model

“…Besides the TGF-β/Smad2 signaling axis, multiple pathways have been reported to role in pulmonary remodeling. For example, Li et al showed that inhibition of MAPK-ERK signaling can reverse high pulmonary blood flow induced pulmonary remodeling [ 31 ]. Moreover, CaMK II was found to promote pulmonary remodeling by exerting its enzyme activity on catalyzing a series of serine or threonine residues in other proteins [ 32 ].…”

Xinmai 'an extract enhances the efficacy of sildenafil in the treatment of pulmonary arterial hypertension via inhibiting MAPK signalling pathway

“…Twenty-eight days later, the rats were weighed (body weight, BW) and anaesthetized by intraperitoneal injection of sodium pentobarbital (40 mg/kg). As described in the previous study (Li et al 2016), a catheter was inserted into the pulmonary artery of the rat and the RV systolic pressure (RVSP) was measured according to the waveform shown on the biological function laboratory system (BL-420, Tai Meng Technology Co., Ltd., Chengdu, China). After RVSP was measured, the hearts were removed from the anaesthetized rats and placed in cold normal saline.…”

“…Recent studies revealed that the process of pulmonary blood vessel formation and remodelling involves multiple signalling pathways, including the mitogen-activated protein kinase (MAPK) signalling pathway, nuclear factor-κB (NF-κB) signalling pathway, and PI3K/AKT signalling pathway (Li et al. 2014 ; 2016 ; Wang et al. 2019 ).…”

Inhibitory effects of formononetin on the monocrotaline‑induced pulmonary arterial hypertension in rats

“…Particularly, ECM deposition and perivascular inflammation have been demonstrated to exert great influence in the pathogenesis of PaH (4,6). Furthermore, multiple reports have demonstrated that certain pathways, including erK and nF-κB, are associated with ECM deposition and inflammation in PAH, providing potential therapeutic targets for PaH (7,8).…”