Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model
- Author:
Hyeryon LEE
1
;
Arim YEOM
;
Kwan Chang KIM
;
Young Mi HONG
Author Information
- Publication Type:Original Article
- Keywords: Hypertension, pulmonary; Endothelin receptor antagonists; Monocrotaline; Gene expression
- MeSH: Animals; Arteries; Arterioles; Blotting, Western; Body Weight; Endothelin Receptor Antagonists; Endothelins; Gene Expression; Heart Ventricles; Humans; Hypertension; Hypertension, Pulmonary; Lung; Models, Animal; Monocrotaline; NADP; NADPH Oxidase; Nitric Oxide Synthase Type III; Oxidoreductases; Rats; Receptors, Endothelin; Victoria
- From:Korean Circulation Journal 2019;49(9):866-876
- CountryRepublic of Korea
- Language:English
- Abstract: BACKGROUND AND OBJECTIVES: Elevated endothelin (ET)-1 level is strongly correlated with the pathogenesis of pulmonary arterial hypertension (PAH). Expression level of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 is increased in the PAH patients. Ambrisentan, a selective endothelin receptor A (ERA) antagonist, is widely used in PAH therapy. The current study was undertaken to evaluate the effects of ambrisentan treatment in the monocrotaline (MCT)-induced PAH rat model. METHODS: Rats were categorized into control group (C), monocrotaline group (M) and ambrisentan group (Am). The M and Am were subcutaneously injected 60 mg/kg MCT at day 0, and in Am, ambrisentan was orally administered the day after MCT injection for 4 weeks. The right ventricle (RV) pressure was measured and pathological changes of the lung tissues were observed by Victoria blue staining. Protein expressions of ET-1, ERA, endothelial nitric oxide synthase (eNOS) and NOX4 were confirmed by western blot analysis. RESULTS: Ambrisentan treatment resulted in a recovery of the body weight and RV/left ventricle+septum at week 4. The RV pressure was lowered at weeks 2 and 4 after ambrisentan administration. Medial wall thickening of pulmonary arterioles and the number of intra-acinar arteries were also attenuated by ambrisentan at week 4. Protein expression levels of ET-1 and eNOS were recovered at weeks 2 and 4, and ERA levels recovered at week 4. CONCLUSIONS: Ambrisentan administration resulted in the recovery of ET-1, ERA and eNOS protein expression levels in the PAH model. However, the expression level of NOX4 remained unaffected after ambrisentan treatment.
