RGD Reference Report - 15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway. - Rat Genome Database

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15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway.

Authors: Wei, Liuping  Yu, Xiufeng  Shi, Hengyuan  Zhang, Bo  Lian, Mingming  Li, Jing  Shen, Tingting  Xing, Yan  Zhu, Daling 
Citation: Wei L, etal., Cell Signal. 2014 Jul;26(7):1476-88. doi: 10.1016/j.cellsig.2014.03.008. Epub 2014 Mar 18.
RGD ID: 11667099
Pubmed: PMID:24657469   (View Abstract at PubMed)
DOI: DOI:10.1016/j.cellsig.2014.03.008   (Journal Full-text)

We have established that 15-hydroxyeicosatetraenoic acid is an important factor in regulation of pulmonary vascular remodeling (PVR) associated with hypoxia-induced pulmonary hypertension (PH), which is further metabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to form 15-ketoeicosatetraenoic acid (15-KETE). However, the role of 15-PGDH and 15-KETE on PH has not been identified. The purpose of this study was to investigate whether 15-PGDH/15-KETE pathway regulates hypoxia-induced PVR in PH and to characterize the underlying mechanisms. To accomplish this, Immunohistochemistry, Ultra Performance Liquid Chromatography, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed. Our results showed that the levels of 15-PGDH expression and endogenous 15-KETE were drastically elevated in the lungs of humans with PH and hypoxic PH rats. Hypoxia stimulated pulmonary arterial smooth muscle cell (PASMC) proliferation, which seemed to be due to the increased 15-PGDH/15-KETE. 15-PGDH/15-KETE pathway was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression. Furthermore, 15-KETE-promoted cell cycle progression and proliferation in PASMCs depended on protease-activated receptor 2 (PAR-2). ERK1/2 signaling was likely required for 15-PGDH/15-KETE-induced PAR-2 expression under hypoxia. Our study indicates that 15-PGDH/15-KETE stimulates the cell cycle progression and proliferation of PASMCs involving ERK1/2-mediated PAR-2 expression, and contributes to hypoxia-induced PVR.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  IEP 11667099mRNA and protein:increased expression:lungRGD 
pulmonary hypertension  ISOHPGD (Homo sapiens)11667099; 11667099mRNA and protein:increased expression:lungRGD 
Pulmonary Hypertension, Hypoxia-Induced  ISOHpgd (Rattus norvegicus)11667099; 11667099mRNA and protein:increased expression:lungRGD 
Pulmonary Hypertension, Hypoxia-Induced  IEP 11667099mRNA and protein:increased expression:lungRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of vascular associated smooth muscle cell proliferation  IMP 11667099 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hpgd  (15-hydroxyprostaglandin dehydrogenase)

Genes (Mus musculus)
Hpgd  (hydroxyprostaglandin dehydrogenase 15 (NAD))

Genes (Homo sapiens)
HPGD  (15-hydroxyprostaglandin dehydrogenase)


Additional Information