title: Combined hypoxia inducible factor-1α and homogeneous endothelial progenitor cell therapy attenuates shunt flow-induced pulmonary arterial hypertension in rabbits.
abstract: BACKGROUND
  Hyperkinetic pulmonary arterial hypertension (PAH) is a common complication in congenital heart disease, and affects operations, indications, and prognoses for patients. Gene-based stem cell transplantation is an alternative treatment that can attenuate PAH.
  
  
  METHODS
  Hyperkinetic PAH rabbit models were successfully established, using common carotid artery and jugular vein anastomosis. Endothelial progenitor cells (EPCs) were isolated from the bone marrow, cultured, and transfected with human hypoxia inducible factor-1 alpha (hHIF-1α), using lentiviruses. Two weeks after the transfected EPCs were transplanted into the rabbits, catheterization was applied to collect hemodynamic data. The hypertrophy of the right ventricle and pulmonary vascular remodeling were evaluated by measuring the right ventricle hypertrophy index, the medial wall thickness, and the medial wall area. Western blot and immunohistochemistry analyses were used to detect the expression of hHIF-1α in the pulmonary small arteries.
  
  
  RESULTS
  Two weeks after transplantation, systolic pulmonary arterial pressure and mean pulmonary arterial pressure were both attenuated. The hypertrophy of the right ventricle, and pulmonary vascular remodeling were reversed. Expression of hHIF-1α in the hHIF-1α-transfected EPCs that had been transplanted was high, and the number of pulmonary small arteries had increased. In addition, combined HIF-1α and homogeneous EPC therapy was more effective at attenuating PAH and increasing the density of pulmonary small arteries, compared with EPC transplantation alone.
  
  
  CONCLUSIONS
  Both the therapy with HIF-1α-transfected EPCs, and EPC transplantation, attenuated shunt flow-induced PAH, by means of an angiogenic effect. The former therapeutic method was more effective.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Guangqing
authors.initials: G
authors.lastname: Cao
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Chuanzhen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Wan
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Hourong
authors.initials: H
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Tang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Bing
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Shuming
authors.initials: S
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China. Electronic address: xinyanpang001@126.com.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Division of Medicine, Department of Cardiovascular Surgery, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China. Electronic address: zhangxq0511@163.com.
authors.forename: Xiquan
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000378:metabolism / Q000637:transplantation*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000503:physiopathology*; D011652:Pulmonary Circulation; D011817:Rabbits; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Congenital heart disease; HIF-1α; endothelial progenitor cells; pulmonary arterial hypertension; rabbits