Sildenafil improves long-term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension. |
| Authors: |
Yen, CH Tsai, TH Leu, S Chen, YL Chang, LT Chai, HT Chung, SY Chua, S Tsai, CY Chang, HW Ko, SF Sun, CK Yip, HK
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| Citation: |
Yen CH, etal., Cytotherapy. 2013 Feb;15(2):209-23. doi: 10.1016/j.jcyt.2012.09.002. Epub 2012 Dec 11. |
| RGD ID: |
8662411 |
| Pubmed: |
PMID:23321332 (View Abstract at PubMed) |
| DOI: |
DOI:10.1016/j.jcyt.2012.09.002 (Journal Full-text) |
BACKGROUND AIMS: We hypothesized that the long-term therapeutic effect of combined sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) on monocrotaline (MCT)-induced rat pulmonary arterial hypertension (PAH) is superior to either treatment alone. METHODS: Male Sprague-Dawley rats (n = 40) were equally divided into normal controls, MCT (65 mg/kg, subcutaneously) only, MCT + sildenafil (25 mg/kg/day, orally), MCT + BMDEPCs (2.0 x 10(6) autologous cells, intravenously) and MCT + sildenafil+ BMDEPCs. BMDEPCs and sildenafil were given on day 21 after MCT administration. Animals were sacrificed by day 90 after MCT administration. RESULTS: The apoptotic (caspase 3, Bax) and inflammatory (tumor necrosis factor-alpha, matrix metalloproteinase-9) biomarkers in right ventricle and lung and pulmonary expressions of fibrotic biomarkers (transforming growth factor-beta, p-Smad3) and connexin 43 protein were lower in monotherapy groups (i.e., MCT + sildenafil and MCT + BMDEPCs) and further decreased in normal controls and combined treatment groups (i.e., MCT + sildenafil + BMDEPCs) compared with untreated animals (i.e., MCT only) (all P < 0.01). Expressions of anti-fibrotic biomarkers (bone morphogenetic protein-2, p-Smad1/5) and numbers of alveolar sacs and arterioles in lung were higher in monotherapy groups and further increased in normal controls and combined treatment groups compared with untreated animals (all P < 0.005). In right ventricle, connexin 43 and alpha-myosin heavy chain (MHC) expressions were higher in the monotherapy groups and further elevated in normal controls and combined treatment groups compared with untreated animals, whereas beta-MHC exhibited the opposite pattern (all P < 0.01). Right ventricular systolic pressure and weight were lower in the monotherapy animals and further reduced in normal controls and combined treatment groups compared with untreated animals (all P < 0.0001). CONCLUSIONS: Combined therapy with BMDEPCs and sildenafil was superior to either treatment alone in attenuating rodent MCT-induced PAH.
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| Genes (Rattus norvegicus) |
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| Gja1 (gap junction protein, alpha 1) |
| Genes (Mus musculus) |
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| Gja1 (gap junction protein, alpha 1) |
| Genes (Homo sapiens) |
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| GJA1 (gap junction protein alpha 1) |
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