title: Sildenafil improves long-term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension.
abstract: OBJECTIVE
  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 × 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-α, matrix metalloproteinase-9) biomarkers in right ventricle and lung and pulmonary expressions of fibrotic biomarkers (transforming growth factor-β, 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 α-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 β-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.
authors: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan.
authors: Chia-Hung
authors: CH
authors: Yen
authors: Tzu-Hsien
authors: TH
authors: Tsai
authors: Steve
authors: S
authors: Leu
authors: Yung-Lung
authors: YL
authors: Chen
authors: Li-Teh
authors: LT
authors: Chang
authors: Han-Tan
authors: HT
authors: Chai
authors: Sheng-Ying
authors: SY
authors: Chung
authors: Sarah
authors: S
authors: Chua
authors: Ching-Yen
authors: CY
authors: Tsai
authors: Hsueh-Wen
authors: HW
authors: Chang
authors: Sheung-Fat
authors: SF
authors: Ko
authors: Cheuk-Kwan
authors: CK
authors: Sun
authors: Hon-Kan
authors: HK
authors: Yip
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000166:cytology / Q000637:transplantation*; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology; D013450:Sulfones / Q000008:administration & dosage*; D013995:Time; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D016686:Monocrotaline; D000068677:Sildenafil Citrate