Early combined treatment with cilostazol and bone marrow-derived endothelial progenitor cells markedly attenuates pulmonary arterial hypertension in rats.
We investigated whether early combined cilostazol and bone marrow-derived endothelial progenitor cell (BMDEPC) treatment offers synergistic benefit in ameliorating monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Male Sprague-Dawley rats (n = 10/group) were randomized to receive saline injection only (group 1), MCT (70 mg/kg) (group 2), and MCT plus cilostazol (20 mg/kg/day) (group 3), MCT plus BMDEPCs (2.0 x 10(6) cells) (group 4), and MCT plus combined cilostazol/BMDEPCs (group 5). Intravenous BMDEPCs and oral cilostazol were given on day 3 after MCT administration. By day 42, connexin43 protein expression in right ventricle (RV) was reduced in group 2 compared with other groups and also was decreased in groups 3 and 4 compared with groups 1 and 5 (all p < 0.05). In addition, mRNA expressions of matrix metalloproteinase-9, tumor necrosis factor-alpha, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric-oxide synthase were lower in lung and RV in group 2 compared with the other groups (all p < 0.05). The number of alveolar sacs and lung arterioles was lower in group 2 than in other groups and lower in groups 3 and 4 than in group 5 (all p < 0.05). RV systolic pressure (RVSP) and weight were increased in group 2 compared with the other groups (all p < 0.0001). Moreover, RVSP and RV-to-left ventricle plus septum weight ratio were higher in groups 3 and 4 than in groups 1 and 5 (p < 0.001) but showed no difference between groups 1 and 5. In conclusion, early combined autologous BMDEPC/cilostazol treatment is superior to BMDEPC or cilostazol only for preventing MCT-induced PAH.
Sun
Cheuk-Kwan
CK
Division of General , Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China.
Lee
Fan-Yen
FY
Sheu
Jiunn-Jye
JJ
Yuen
Chun-Man
CM
Chua
Sarah
S
Chung
Sheng-Ying
SY
Chai
Han-Tan
HT
Chen
Yen-Ta
YT
Kao
Ying-Hsien
YH
Chang
Li-Teh
LT
Yip
Hon-Kan
HK
D000818:Animals; D016026:Bone Marrow Transplantation / Q000502:physiology*; D000077407:Cilostazol; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000637:transplantation; D005456:Fluorescent Dyes; D018380:Hematopoietic Stem Cell Transplantation; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000628:therapy*; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016686:Monocrotaline; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011042:Poisons; D011650:Pulmonary Alveoli / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D005456:Fluorescent Dyes; D008565:Membrane Proteins; D011042:Poisons; D013777:Tetrazoles; D014665:Vasodilator Agents; D016686:Monocrotaline; D000077407:Cilostazol