RGD Reference Report - Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats. - Rat Genome Database

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Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats.

Authors: Wang, Dongzhi  Li, Hailing  Weir, E Kenneth  Xu, Yawei  Xu, Dachun  Chen, Yingjie 
Citation: Wang D, etal., Int J Cardiol. 2019 Nov 15;295:14-20. doi: 10.1016/j.ijcard.2019.07.078. Epub 2019 Jul 27.
RGD ID: 151347602
Pubmed: PMID:31402164   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ijcard.2019.07.078   (Journal Full-text)

Patients with pulmonary arterial hypertension (PAH) and right ventricular (RV) failure have a poor clinical outcome, but the mechanisms of PAH and RV failure development are not totally clear. PAH is associated with reduced NO bioavailability and increased endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays a critical role in ADMA degradation. Here we generated a novel DDAH1 deficiency rat strain using the CRISPR-Cas9 technique, and studied the effect of DDAH1 dysfunction on monocrotaline-induced PAH, lung vascular remodeling and RV hypertrophy. DDAH1 knockout resulted in abolished DDAH1 expression in various tissues, and significant increases of plasma and lung ADMA content. DDAH1 knockout has no detectable effect on cardiac and lung structure, and LV function under control conditions in rats. However, DDAH1 knockout significantly aggravated monocrotaline-induced lung and RV oxidative stress, lung vascular remodeling and fibrosis, pulmonary hypertension and RV hypertrophy in rats. DDAH1 KO resulted in significantly greater increases of plasma and lung ADMA content under control conditions. In the wild type rats monocrotaline resulted in significant increases of plasma and lung ADMA contents and reduction of lung eNOS protein content and these changes were more marked in DDAH1 KO rats. Together, our results demonstrated that DDAH1 plays an important role in attenuating monocrotaline-induced lung oxidative stress, pulmonary hypertension and RV hypertrophy in rats.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Pulmonary Arterial Hypertension exacerbatesISODdah1 (Rattus norvegicus)151347602; 151347602compared to wild typeRGD 
Pulmonary Arterial Hypertension exacerbatesIMPmonocrotaline151347602; 151347602; 151347602compared to wild typeRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Objects Annotated

Genes (Rattus norvegicus)
Ddah1  (dimethylarginine dimethylaminohydrolase 1)
Ddah1em1Ywxu  (dimethylarginine dimethylaminohydrolase 1; CRISPR/Cas9 induced mutant 1, Ywxu)

Genes (Mus musculus)
Ddah1  (dimethylarginine dimethylaminohydrolase 1)

Genes (Homo sapiens)
DDAH1  (dimethylarginine dimethylaminohydrolase 1)

Strains
SD-Ddah1em1Ywxu  (NA)


Additional Information