Early Combined Treatment with Cilostazol and Bone Marrow-Derived Endothelial Progenitor Cells Markedly Attenuates Pulmonary Arterial Hypertension in Rats
- Cheuk-Kwan Sun,
- Fan-Yen Lee,
- Jiunn-Jye Sheu,
- Chun-Man Yuen,
- Sarah Chua,
- Sheng-Ying Chung,
- Han-Tan Chai,
- Yen-Ta Chen,
- Ying-Hsien Kao,
- Li-Teh Chang and
- Hon-Kan Yip
- Divisions of General Surgery (C.-K.S.), Thoracic and Cardiovascular Surgery (F.-Y.L., J.-J.S.), Neurosurgery (C.-M.Y.), and Urology (Y.-T.C.), Department of Surgery and Division of Cardiology, Department of Internal Medicine (S.C., S.-Y.C., H.-T.C., H.-K.Y.) and Department of Anesthesiology (Y.-H.K.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; and Basic Science, Department of Nursing, Meiho Institute of Technology, Pingtung, Taiwan, Republic of China (L.-T.C.)
- Address correspondence to:
Dr. Hon-Kan Yip, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta Pei Rd., Niao Sung Hsiang, Kaohsiung Hsien 83301, Taiwan. E-mail: han.gung{at}msa.hinet.net
Abstract
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 × 106 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-α, 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.
Footnotes
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This work was supported by the Chang Gung Medical Research [Proposal Grant CMRPG 870211] (from Chang Gung Memorial Hospital and Chang Gung University). C.-K.S. and F.-Y.L. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.154328.
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ABBREVIATIONS: PAH, pulmonary arterial hypertension; MCT, monocrotaline; BMDEPC, bone marrow-derived endothelial progenitor cell; SD, Sprague-Dawley; BMDMNC, bone marrow-derived mononuclear cell; PBS, phosphate-buffered saline; VEGF, vascular endothelial growth factor; EPC, endothelial progenitor cell; acLDL, acetylated low-density lipoprotein; PFA, paraformaldehyde; Dil, 1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine; vWF, von Willebrand factor; RVSP, right ventricular systolic pressure; RV, right ventricle; PCR, polymerase chain reaction; HPF, high-power field; MMP, matrix metalloproteinase; eNOS, endothelial nitric-oxide synthase; TNF, tumor necrosis factor; Cx, connexin.
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- Received March 29, 2009.
- Accepted June 12, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
