Enhanced protection against pulmonary hypertension with sildenafil and endothelial progenitor cell in rats

• Published in: International journal of cardiology 2012-12, Vol.162 (1), p.45-58
• Main Authors: Sun, Cheuk-Kwan, Lin, Yu-Chun, Yuen, Chun-Man, Chua, Sarah, Chang, Li-Teh, Sheu, Jiunn-Jye, Lee, Fan-Yen, Fu, Morgan, Leu, Steve, Yip, Hon-Kan
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone marrow cells; Cardiology. Vascular system; Cardiovascular; Combined Modality Therapy; Endothelial Cells - transplantation; Heart; Hypertension, Pulmonary - prevention & control; Male; Medical sciences; Monocrotaline; Phosphodiesterase inhibitor; Piperazines - therapeutic use; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Purines - therapeutic use; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Stem Cell Transplantation; Sulfones - therapeutic use; Vasodilator Agents - therapeutic use
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2011.05.002

Abstract Background Sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) have been shown to ameliorate monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in the rat. We test whether combined sildenafil and BMDEPC treatment exerts additional protection against MCT-induced PAH in rats. Methods Male Sprague–Dawley rats were randomized to receive saline injection only (group 1), MCT (70 mg/kg) only (group 2), MCT plus autologous BMDEPC (2.0 × 106 cells) transplantation (group 3), MCT with sildenafil (30 mg/kg/day) (group 4), and MCT with combined BMDEPCs–sildenafil (30 mg/kg/day) (group 5). Intravenous BMDEPC and oral sildenafil were given on day 3 after MCT administration. Hemodynamics were analyzed using Labchart software, whereas cellular and molecular parameters were measured using flow cytometry, real-time PCR, TUNEL assay, Western blot, and immunohistochemical staining. Results By day 35 following MCT treatment, lower expression of connexin43, protein kinase C-ε, Bcl-2, and endothelial nitric oxide synthase and higher expression of tumor necrosis factor-α and caspase 3 were found in right ventricle (RV) and lung in group 2 compared with other groups (all p < 0.05). The number of alveolar sacs and lung arterioles were also lower in group 2 than in other groups (all p < 0.05). Furthermore, RV systolic pressure (RVSP), RV weight, and RV-to-final body weight ratio were substantially increased in group 2 than in other groups, and notably higher in groups 3 and 4 than in groups 1 and 5 (all p < 0.0001). Conclusions Combined therapy with autologous BMDEPC and sildenafil is superior to either BMDPEC or sildenafil alone for preventing MCT-induced PAH.