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

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.

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Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: Role of mitogen-activated protein kinases and cell cycle regulators

Steroids ◽

10.1016/j.steroids.2005.02.012 ◽

2005 ◽

Vol 70 (5-7) ◽

pp. 418-426 ◽

Cited By ~ 61

Author(s):

E FAIVRE ◽

A SKILDUM ◽

L PIERSONMULLANY ◽

C LANGE

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Progesterone Receptor ◽

Protein Kinases ◽

Cell Cycle Regulators ◽

Cell Models ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein ◽

Rapid Signaling

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Buddleja officinalis suppresses high glucose-induced vascular smooth muscle cell proliferation: role of mitogen-activated protein kinases, nuclear factor-κB and matrix metalloproteinases

Experimental Biology and Medicine ◽

10.1258/ebm.2009.009222 ◽

2010 ◽

Vol 235 (2) ◽

pp. 247-255 ◽

Cited By ~ 13

Author(s):

Yun Jung Lee ◽

Jin Sook Kim ◽

Dae Gill Kang ◽

Ho Sub Lee

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Matrix Metalloproteinases ◽

Protein Kinases ◽

High Glucose ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein

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Enhancement of erythropoietin-stimulated cell proliferation by Anandamide correlates with increased activation of the mitogen-activated protein kinases ERK1 and ERK2

The Hematology Journal ◽

10.1038/sj.thj.6200036 ◽

2000 ◽

Vol 1 (4) ◽

pp. 254-263 ◽

Cited By ~ 6

Author(s):

Peter Valk ◽

Sandra Verbakel ◽

Marieke von Lindern ◽

Bob Löwenberg ◽

Ruud Delwel

Keyword(s):

Cell Proliferation ◽

Protein Kinases ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein

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Role of Mitogen-activated Protein Kinases in 4-Hydroxy-2-nonenal-induced Actin Remodeling and Barrier Function in Endothelial Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m311184200 ◽

2003 ◽

Vol 279 (12) ◽

pp. 11789-11797 ◽

Cited By ~ 105

Author(s):

Peter V. Usatyuk ◽

Viswanathan Natarajan

Keyword(s):

Endothelial Cells ◽

Protein Kinases ◽

Barrier Function ◽

Actin Remodeling ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein

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Role of Mitogen-Activated Protein Kinases and Tyrosine Kinases on IL-1-Induced NF-κB Activation and iNOS Expression in Bovine Articular Chondrocytes

Nitric Oxide ◽

10.1006/niox.2001.0378 ◽

2002 ◽

Vol 6 (1) ◽

pp. 35-44 ◽

Cited By ~ 30

Author(s):

A.Ferreira Mendes ◽

M.Margarida Caramona ◽

A.Pato Carvalho ◽

M.Celeste Lopes

Keyword(s):

Protein Kinases ◽

Tyrosine Kinases ◽

Articular Chondrocytes ◽

Inos Expression ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein ◽

Bovine Articular Chondrocytes

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Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00527.2016 ◽

2017 ◽

Vol 313 (5) ◽

pp. L899-L915 ◽

Cited By ~ 8

Author(s):

Fumiaki Kato ◽

Seiichiro Sakao ◽

Takao Takeuchi ◽

Toshio Suzuki ◽

Rintaro Nishimura ◽

...

Keyword(s):

Flow Cytometry ◽

Endothelial Cell ◽

Vascular Remodeling ◽

Time Dependent ◽

Causative Role ◽

Dependent Manner ◽

Vascular Endothelial ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by progressive obstructive remodeling of pulmonary arteries. However, no reports have described the causative role of the autophagic pathway in pulmonary vascular endothelial cell (EC) alterations associated with PAH. This study investigated the time-dependent role of the autophagic pathway in pulmonary vascular ECs and pulmonary vascular EC kinesis in a severe PAH rat model (Sugen/hypoxia rat) and evaluated whether timely induction of the autophagic pathway by rapamycin improves PAH. Hemodynamic and histological examinations as well as flow cytometry of pulmonary vascular EC-related autophagic pathways and pulmonary vascular EC kinetics in lung cell suspensions were performed. The time-dependent and therapeutic effects of rapamycin on the autophagic pathway were also assessed. Sugen/hypoxia rats treated with the vascular endothelial growth factor receptor blocker SU5416 showed increased right ventricular systolic pressure (RVSP) and numbers of obstructive vessels due to increased pulmonary vascular remodeling. The expression of the autophagic marker LC3 in ECs also changed in a time-dependent manner, in parallel with proliferation and apoptotic markers as assessed by flow cytometry. These results suggest the presence of cross talk between pulmonary vascular remodeling and the autophagic pathway, especially in small vascular lesions. Moreover, treatment of Sugen/hypoxia rats with rapamycin after SU5416 injection activated the autophagic pathway and improved the balance between cell proliferation and apoptosis in pulmonary vascular ECs to reduce RVSP and pulmonary vascular remodeling. These results suggested that the autophagic pathway can suppress PAH progression and that rapamycin-dependent activation of the autophagic pathway could ameliorate PAH.

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