Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Abstract

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.

Effect of RNA interference with HIF-1α on the growth of pulmonary artery endothelial cells in broiler chickens

“…MAPK pathways were significantly enriched in our results. One study found that MAPK inhibitors reversed hypoxia-induced pulmonary hypertension in rats ( Silva et al, 2022 ). This also demonstrates a potential correlation between the MAPK signaling pathway and the development of BAS.…”

Expression Profiles of circRNAs and Identification of hsa_circ_0007608 and hsa_circ_0064656 as Potential Biomarkers for COPD-PH Patients

“…[35][36][37] As inflammation mediators, NF-κB, TGF-β, MAPK and TNF can regulate the functions of pulmonary vascular cells, including cellular proliferation, apoptosis and migration, contributing to pulmonary vascular remodeling. [38][39][40][41] Interestingly, those 4 cytokines mentioned above also can induce or participate in the conversion process of endothelial cells into mesenchymal fibroblast-like cells, which is an important pathologic change of pulmonary vascular remodeling. More specifically, NF-κB, a cellular transcription factor regulating inflammation, plays a central role in inflammation-mediated EndMT, the stimulation of which and the subsequent production of cytokines are the key step in EndMT.…”

Expression profiles of circRNAs and identification of hsa_circ_0007608 and hsa_circ_0064656 as potential biomarkers for COPD-PH patients

“…Additionally, release of calcium ions from the endoplasmic reticulum to the cytoplasm and mitochondria is an important mediators of cell proliferation, migration and mesenchymal transition, thereby affecting the contractility and resistance of pulmonary artery [38][39] . As inflammation mediators, NF-kB, TGF-β, MAPK and TNF can regulate the functions of pulmonary vascular cells, including celluar proliferation,apoptosis and migration, contributing to pulmonary vascular remodeling [40][41][42][43] .…”