title: Effect of early administration of lower dose versus high dose of fresh mitochondria on reducing monocrotaline-induced pulmonary artery hypertension in rat.
abstract: OBJECTIVE
  This study aim to investigate whether early mitochondrial administration would be effective and whether high-dose mitochondria (15000 μg/rat) would be more effective than low-dose mitochondria (1500 μg/rat) for attenuating the monocrotaline (MCT/65 mg/kg/rat)-induced pulmonary artery hypertension (PAH) in rat.
  
  
  RESULTS
  Male-adult SD rats (n = 32) were randomized categorized into groups 1 (sham-control), 2 (PAH), 3 (PAH + low-dose mitochondria), and 4 (PAH + high-dose mitochondria). Mitochondria were admitted at day 5 and rats were sacrificed at day 35 post-MCT treatment. By day 35, oxygen saturation (saO2) was highest in group 1 and lowest in group 2, and significantly higher in group 3 than in group 4 (P<0.001). Conversely, right ventricular systolic blood pressure showed an opposite pattern compared with saO2among all groups (P<0.001). Histological integrity of alveolar sacs exhibited a pattern identical to saO2, whereas lung crowding score and number of muscularized artery displayed an opposite pattern (all P<0.001). The protein expression of indices of inflammation (MMP-9, TNF-α, NF-κB), oxidative stress (oxidized protein, NO-1, NOX-2, NOX-4), apoptosis (Bax, cleaved caspase-3 and PARP), fibrosis (p-Smad3, TGF-β), mitochondrial-damage (cytosolic cytochrome-C), and hypoxia-smooth muscle proliferative factors (HIF-α, connexin43, TRPCs) showed an opposite pattern compared, whereas anti-fibrosis (p-Smad1/5, BMP-2) and mitochondrial integrity (mitochondrial cytochrome-C) exhibited an identical pattern to saO2in all groups (all P<0.001).
  
  
  CONCLUSIONS
  Low dose is superior to high dose of mitochondria for protecting against MCT-induced PAH. The paradoxical beneficial effect may imply therapy with 15000 μg/rat mitochondria is overdose in this situation.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Tien-Hung
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Han-Tan
authors.initials: HT
authors.lastname: Chai
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Sheu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Divisions of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301 Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University Kaohsiung 80424, Taiwan.
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Meng-Shen
authors.initials: MS
authors.lastname: Tong
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Sung
authors.affiliation: Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students Kaohsiung Taiwan.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Lu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical UniversityTaichung 40402, Taiwan.
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
keywords: Mitochondria; oxidative stress; pulmonary arterial hypertension; smooth muscle proliferation