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The effect of sildenafil on the right ventricle hypertrophy and pressure in a monocrotaline-induced pulmonary hypertension rat model

Title
The effect of sildenafil on the right ventricle hypertrophy and pressure in a monocrotaline-induced pulmonary hypertension rat model
Authors
배현경
Issue Date
2017
Department/Major
대학원 의학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
홍영미
Abstract
Pulmonary arterial hypertension (PAH) leads to the hypertrophy and dysfunction of the right ventricle, as well as the elevation of the pulmonary vascular resistance and right ventricular pressure (RVP). The purpose was to study the effect of sildenafil on the right ventricular hypertrophy (RVH) and high RVP in a monocrotaline (MCT)-induced PAH rat model. The effect of different dosages of sildenafil was also investigated in this PAH models. The rats were divided randomly into 3 groups. The control group (C), the monocrotaline group (M) (subcutaneous injection of 60 mg/kg of MCT) and the sildenafil group (S) (subcutaneous injection of MCT 60 mg/kg + gavage feeding of sildenafil). The S group was subdivided into 2 subgroups: S10, S30 (10, 30 mg/kg/day each for 28 days). RVP, body weight (BW) and organ weights including right ventricle (RV)/body weight (BW), RV/ left ventricle+septum (LV+ S), LV+S/BW and lung/BW were measured. Histopathologic analysis of the pulmonary arteries, Masson Trichrome staining of the RV tissue, immunohistochemical staining of the lung tissue and western blot analysis of the RV tissue were performed. The mean RVP in the S group compared with the M group was significantly lower: S10 (13.7±1.5 mmHg vs. 17.0±0.0 mmHg; P< 0.05) and S30 (13.0±1.0 mmHg vs. 17.0±0.0 mmHg, P<0.05) at week 1, S10 (13.0±1.0 mmHg vs. 25.3±1.5 mmHg, P< 0.05) and S30 (13.0±1.0 mmHg vs. 25.3±1.5 mmHg, P<0.05) at week 2, S10 (13.0±1.0 mmHg vs.39.7±8.5 mmHg, P< 0.05) and S30 (13.1±1.5 mmHg vs. 39.7±8.5 mmHg, P<0.05) at week 4. The RV/ BW in the S group was greatly reduced in comparison with the M group at week 4: S10 (1.5±0.3 g vs. 1.8±0.1 g; P< 0.05) and S30 (1.4±0.3 g vs. 1.8±0.1 g, P< 0.05). Although the RV/LV+S in the S30 group was lowered in comparison with the M group at week 4, the result was not statistically significant. The number of intra-acinar arteries of the pulmonary arterioles of the S group when compared with M group, it significantly lessened: S10 (1.5±0.1 vs. 1.9±0.2, P< 0.05) and S30 (1.1±0.1 vs. 1.9±0.2, P<0.05) group at week 2, and S30 (1.1±0.4 vs. 2.0±0.3, P<0.05) at week 4. The medial wall thickness of the pulmonary arterioles significantly lessened in the S10 (28.4±4.6 vs. 45.0±4.8; P< 0.05) and S30 (35.4±3.1 vs. 45.0±4.8, P<0.05) at week 2 and S10 (34.4±8.2 vs 42.4±1.9; P< 0.05) and S30 (33.8±0.8 vs. 42.4±1.9, P<0.05) at week 4. The collagen content decreased in the RV tissues in the S30 group at week 4. In immunohistochemical staining of the lung tissue, the protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X (Bax), caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) greatly decreased in the S30 group at week 4. In western blotting of RV tissue, the protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA greatly diminished in the S30 group at week 4. In conclusion, sildenafil alleviated RVH and mean RVP in this study. Sildenafil of 30 mg/kg is presumed to be more appropriate than sildenafil of 10 mg/kg considering histopathologic data of the lung tissues in this current study. This study suggests that sildenafil improves the histopathologic changes of pulmonary artery and RV tissue in MCT induced PAH rat models.;폐동맥 고혈압은 폐혈관 저항을 증가시킬 뿐 아니라 우심실 비대와 우심실 기능 장애를 일으킨다. 본 연구의 목적은 Monocrotaline(MC)유도로 발생한 폐동맥고혈압 쥐 모델에서 sildenafil이 우심실 비대 및 우심실 압력에 어떠한 효과가 있는지 알아보고자 하는 것이다. 또한 Sildenafil 용량에 따른 효과도 관찰하였다. 쥐는 임의로 나누어 대조군 (C), monocrotaline 군 (M: monocrotaline을 60mg/kg 피하 주입), 두개의 sildenafil 그룹(S10, S30: monocrotaline 60 mg/kg 피하 주입 1일 후 각각 sildenafil 10mg/kg/day, 30 mg/kg/day를 28일간 경구 주입)으로 구분했다. 우심실 압력, 조직들의 무게를 측정했고 폐혈관의 조직병리학적 변화를 관찰하였다. 폐조직에서 면역조직화학염색을 시행하고 우심실 조직에서 Masson Trichrome염색, Western blot 분석을 시행했다. 평균 우심실 압력(RVP)은 S10, S30 군에서M군과 비교하여 1, 2, 4주 차에 유의하게 감소하였다. 체중당 우심실 무게는 S10, S30 군에서 4주차에 유의하게 감소하였다. 폐세동맥의 개수는 2주차에 S10, S30 군에서 감소하였고 4주차에 S30 군에서 유의하게 감소했다. 중막의 두께는 2,4주차에 S10, S30 군에서 유의하게 줄어들었다. 우심실 조직의 collagen 량은 S30 군에서 4주차에 유의하게 감소했다. 폐조직의 면역조직화학염색에서 B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA)가 S30 군에서 4주차에 유의하게 감소했다. 우심실 조직 Western blot에서는 troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA 가 S30 군에서 4주차에 유의하게 감소했다. Sildenafil은 우심실 비대를 경감시키고 평균 우심실 압력을 감소시키는 것으로 나타났다. 또한 본 연구에서 조직병리학적 결과를 고려하면 체중당 30mg의 sildenafil 효과가 더 유의하게 나타났다. 이러한 결과들은 MCT유도로 발생한 폐동맥고혈압 쥐 모델에서 sildenafil이 폐동맥과 우심실의 조직변화를 호전시킬 가능성이 있음을 시사한다.
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