Huang Tien-Hung, Chung Sheng-Ying, Chua Sarah, Chai Han-Tan, Sheu Jiunn-Jye, Chen Yi-Ling, Chen Chih-Hung, Chang Hsueh-Wen, Tong Meng-Shen, Sung Pei-Hsun, Sun Cheuk-Kwan, Lu Hung-I, Yip Hon-Kan
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
Am J Transl Res. 2016 Dec 15;8(12):5151-5168. eCollection 2016.
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.
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 (saO) 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 saO among all groups (P<0.001). Histological integrity of alveolar sacs exhibited a pattern identical to saO, 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 saO in all groups (all P<0.001).
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.
本研究旨在探究早期给予线粒体是否有效，以及高剂量线粒体（15000μg/大鼠）在减轻大鼠由野百合碱（MCT/65mg/kg/大鼠）诱导的肺动脉高压（PAH）方面是否比低剂量线粒体（1500μg/大鼠）更有效。
成年雄性SD大鼠（n = 32）被随机分为1组（假手术对照组）、2组（PAH组）、3组（PAH + 低剂量线粒体组）和4组（PAH + 高剂量线粒体组）。在MCT治疗后第5天给予线粒体，在第35天处死大鼠。到第35天时，1组的氧饱和度（saO）最高，2组最低，3组显著高于4组（P<0.001）。相反，所有组中右心室收缩压与saO呈现相反的模式（P<0.001）。肺泡囊的组织学完整性呈现与saO相同的模式，而肺拥挤评分和肌化动脉数量呈现相反的模式（均P<0.001）。炎症指标（MMP - 9、TNF -α、NF -κB）、氧化应激指标（氧化蛋白、NO - 1、NOX - 2、NOX - 4）、凋亡指标（Bax、裂解的半胱天冬酶 - 3和PARP）、纤维化指标（p - Smad3、TGF -β）、线粒体损伤指标（胞质细胞色素 - C）以及缺氧 - 平滑肌增殖因子（HIF -α、连接蛋白43、瞬时受体电位通道蛋白）显示出相反的模式，而抗纤维化指标（p - Smad1/5、BMP - 2）和线粒体完整性指标（线粒体细胞色素 - C）在所有组中呈现与saO相同的模式（均P<0.001）。
低剂量线粒体在预防MCT诱导的PAH方面优于高剂量线粒体。这种矛盾的有益效果可能意味着在这种情况下给予15000μg/大鼠线粒体是过量的。
