Tien-Hung Huang1, Sheng-Ying Chung1, Sarah Chua1, Han-Tan Chai1, Jiunn-Jye Sheu2, Yi-Ling Chen1, Chih-Hung Chen3, Hsueh-Wen Chang4, Meng-Shen Tong1, Pei-Hsun Sung1, Cheuk-Kwan Sun5, Hung-I Lu2, Hon-Kan Yip6. 1. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan. 2. Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan. 3. Divisions of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301 Taiwan. 4. Department of Biological Sciences, National Sun Yat-Sen University Kaohsiung 80424, Taiwan. 5. Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students Kaohsiung Taiwan. 6. 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.
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. METHOD AND 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 saO2 among 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 saO2 in all groups (all P<0.001). CONCLUSION: 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.
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. METHOD AND 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 saO2 among 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 saO2 in all groups (all P<0.001). CONCLUSION: 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: Marius M Hoeper; Harm Jan Bogaard; Robin Condliffe; Robert Frantz; Dinesh Khanna; Marcin Kurzyna; David Langleben; Alessandra Manes; Toru Satoh; Fernando Torres; Martin R Wilkins; David B Badesch Journal: J Am Coll Cardiol Date: 2013-12-24 Impact factor: 24.094