Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway

Abstract

Background:We have previously shown that 15-hydroxyeicosatetraenoic acid (15-HETE) plays a critical role in pulmonary hypertension (PH)-associated vascular remodeling. However, the signaling mechanisms remain unclear. The purpose of this study was to investigate the role of 15-lipoxygenase-2 (15-LO-2)/15-HETE-mitogen-activated protein kinases (MAPKs) pathway in hypoxia-induced pulmonary vascular remodeling and the underlying mechanisms. Methods:The arterial wall thickness was measured by hematoxylin and eosin (HE) staining in distal pulmonary arteries isolated from normal and PAH patient-derived lungs. The protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 mitogen-activated protein kinases (p-p38MAPK) were measured by Western blot in the lungs of PAH patients and hypoxia-induced rats. The apoptosis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Flow cytometry. The cell proliferation and cell cycle in PASMCs following hypoxia were analyzed by bromodeoxyuridine incorporation and flow cytometry, respectively. Results:Our results showed that the levels of p-ERK and p-p38MAPK were both drastically elevated in lungs from human patients and hypoxic rats. The HE staining revealed that the medial wall thickness was higher in patients with PAH than normal humans. In cultured PASMCs, Hypoxia stimulated the cell proliferation, the cell cycle progression, and subsequently promoted cell differentiation and cell migration leading to the suppressed cell apoptosis. Furthermore, MAPKs- induced cell proliferation and anti-apoptosis in PASMCs is 15-LO-2/15HETE activation-dependent. Conclusion:Our study indicates that hypoxia-induced pulmonary vascular remodeling is associated with increased levels of 15-LO-2 and 15-HETE. 15-LO-2/15-HETE stimulates the cell proliferation and anti-apoptosis in PASMCs through phosphorylation of ERK and p38MAPK, which subsequently contributing to hypoxia-induced pulmonary vascular remodeling.

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…A decrease in the infected tissue was also observed for 15-hydroxyeicosatetraenoic acid (15-HETE) (Fig. 8), which other studies have shown participates in vascular remodeling and increases both iNOS and mucin production (83)(84)(85). 15-HETE is also a precursor in lipoxin production and suppresses epithelial differentiation (86 -89).…”

Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

“…The confluent human PASMCs cultured in 6-well plates were wounded by pipette tips, creating an acellular 1-mm-wide lane per well, and the detached cells were washed out by PBS [21]. Then the cells were transfected with si-NC or si-lncRNA MEG3 under both normal and hypoxic conditions.…”

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

“…Then, the TdT-labelled nucleotide mix was added to each slide and incubated at 37°C for 60 min in a dark environment. The slides were washed twice with PBS and then counterstained with 10 mg/ml 4,6-diamidino-2-phenylindole (DAPI) for 5 min at 37°C [23]. …”