RGD Reference Report - Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension. - Rat Genome Database

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Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.

Authors: Masaki, Takeshi  Okazawa, Makoto  Asano, Ryotaro  Inagaki, Tadakatsu  Ishibashi, Tomohiko  Yamagishi, Akiko  Umeki-Mizushima, Saori  Nishimura, Manami  Manabe, Yusuke  Ishibashi-Ueda, Hatsue  Shirai, Manabu  Tsuchimochi, Hirotsugu  Pearson, James T  Kumanogoh, Atsushi  Sakata, Yasushi  Ogo, Takeshi  Kishimoto, Tadamitsu  Nakaoka, Yoshikazu 
Citation: Masaki T, etal., Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2023899118. doi: 10.1073/pnas.2023899118.
RGD ID: 401940192
Pubmed: PMID:33836606   (View Abstract at PubMed)
PMCID: PMC7980441   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.2023899118   (Journal Full-text)

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague-Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague-Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr-/- ) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr-/- rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AHRHumanPulmonary Arterial Hypertension severityIEP protein:increased activity:serum (human)RGD 
AhrMousePulmonary Arterial Hypertension severityISOAHR (Homo sapiens)protein:increased activity:serum (human)RGD 
AhrRatPulmonary Arterial Hypertension severityISOAHR (Homo sapiens)protein:increased activity:serum (human)RGD 
AHRHumanpulmonary hypertension amelioratesISOAhr (Rattus norvegicus)compared to wild type littermatesRGD 
AHRHumanpulmonary hypertension  ISOAhr (Rattus norvegicus)6-formylindolo[3 more ...RGD 
AhrRatpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
AhrMousepulmonary hypertension  ISOAhr (Rattus norvegicus)6-formylindolo[3 more ...RGD 
AhrMousepulmonary hypertension amelioratesISOAhr (Rattus norvegicus)compared to wild type littermatesRGD 
AhrRatpulmonary hypertension  IMP 6-formylindolo[3 more ...RGD 
Ahrem1IexasRatpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
SD-Ahrem1Iexas-/-Ratpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
AHRHumanPulmonary Hypertension, Hypoxia-Induced treatmentISOAhr (Rattus norvegicus) RGD 
AhrMousePulmonary Hypertension, Hypoxia-Induced treatmentISOAhr (Rattus norvegicus) RGD 
AhrRatPulmonary Hypertension, Hypoxia-Induced treatmentIMP  RGD 
CYP1A1HumanPulmonary Hypertension, Hypoxia-Induced  ISOCyp1a1 (Rattus norvegicus)mRNA:increased expression:lung (rat)RGD 
Cyp1a1RatPulmonary Hypertension, Hypoxia-Induced  IEP mRNA:increased expression:lung (rat)RGD 
Cyp1a1MousePulmonary Hypertension, Hypoxia-Induced  ISOCyp1a1 (Rattus norvegicus)mRNA:increased expression:lung (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
KDRHumansemaxanib  ISOKdr (Rattus norvegicus)su5416 more ...RGD 
KdrRatsemaxanib  EXP su5416 more ...RGD 
KdrMousesemaxanib  ISOKdr (Rattus norvegicus)su5416 more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AhrRatincreased right ventricle systolic pressure amelioratesIMP compared to wild type littermatesRGD 
Ahrem1IexasRatincreased right ventricle systolic pressure amelioratesIMP compared to wild type littermatesRGD 
SD-Ahrem1Iexas-/-Ratincreased right ventricle systolic pressure amelioratesIMP compared to wild type littermatesRGD 
AhrRatpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
Ahrem1IexasRatpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
SD-Ahrem1Iexas-/-Ratpulmonary hypertension amelioratesIMP compared to wild type littermatesRGD 
Objects Annotated

Genes (Rattus norvegicus)
Ahr  (aryl hydrocarbon receptor)
Ahrem1Iexas  (aryl hydrocarbon receptor; CRISPR/Cas9 induced mutant1, Iexas)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Kdr  (kinase insert domain receptor)

Genes (Mus musculus)
Ahr  (aryl-hydrocarbon receptor)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Kdr  (kinase insert domain protein receptor)

Genes (Homo sapiens)
AHR  (aryl hydrocarbon receptor)
CYP1A1  (cytochrome P450 family 1 subfamily A member 1)
KDR  (kinase insert domain receptor)

Strains
SD-Ahrem1Iexas-/-  (NA)

Objects referenced in this article
Strain SD-Ahrem1Iexas+/+ null Rattus norvegicus
Strain SD-Ahrem1Iexas+/- null Rattus norvegicus

Additional Information