Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan.
Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan.
J Thorac Cardiovasc Surg. 2022 May;163(5):e361-e373. doi: 10.1016/j.jtcvs.2020.08.014. Epub 2020 Aug 12.
Because mitochondrial dysfunction is a key factor in the progression of pulmonary hypertension, this study tested the hypothesis that transplantation of exogenous viable mitochondria can reverse pulmonary artery remodeling and restore right ventricular performance in pulmonary hypertension.
Pulmonary hypertension was induced by parenteral injection of monocrotaline (60 mg/kg) and creation of a left-to-right shunt aortocaval fistula in rats. Three weeks after creation of fistula, the animals were randomly assigned to receive intravenous delivery of placebo solution or allogeneic mitochondria once weekly for 3 consecutive weeks. Mitochondria (100 μg) were isolated from the freshly harvested soleus muscles of naïve rats. Transthoracic echocardiography was performed at 3 weeks after mitochondrial delivery.
Ex vivo heart-lung block images acquired by an IVIS Spectrum (PerkinElmer, Waltham, Mass) imaging system confirmed the enhancement of MitoTracker (Invitrogen, Carlsbad, Calif) fluorescence in the pulmonary arteries. Mitochondria transplantation significantly increased lung tissue adenosine triphosphate concentrations and improved right ventricular performance, as evidenced by a reduction in serum levels of B-type natriuretic peptide and ventricular diameter. Right ventricular mass and wall thickness were restored in the mitochondrial group. In the pulmonary arteries of rats that received mitochondrial treatment, vascular smooth muscle cells expressed higher levels of α-smooth muscle actin and smooth muscle myosin heavy chain II, indicating the maintenance of the nonproliferative, contractile phenotype. The hyper-reactivity of isolated pulmonary arteries to α-adrenergic stimulation was also attenuated after mitochondrial transplantation.
Transplantation of viable mitochondria can restore the contractile phenotype and vasoreactivity of the pulmonary artery, thereby reducing the afterload and right ventricular remodeling in rats with established pulmonary hypertension. The improvement in overall right ventricular performance suggests that mitochondrial transplantation can be a revolutionary clinical therapeutic option for the management of pulmonary hypertension.
由于线粒体功能障碍是肺动脉高压进展的关键因素，本研究检验了这样一个假设，即移植外源性存活线粒体可以逆转肺动脉重构并恢复肺动脉高压中的右心室功能。
通过静脉注射野百合碱（60mg/kg）和建立左向右分流的腹主动脉-腔静脉瘘在大鼠中诱导肺动脉高压。瘘管形成后 3 周，动物随机分为每周接受静脉注射安慰剂溶液或同种异体线粒体 3 周的 3 个连续疗程。线粒体（100μg）从新鲜收获的大鼠比目鱼肌中分离出来。在给予线粒体后 3 周进行经胸超声心动图检查。
使用 IVIS Spectrum（PerkinElmer，Waltham，Mass）成像系统进行的离体心肺阻断图像证实了肺动脉中 MitoTracker（Invitrogen，Carlsbad，Calif）荧光的增强。线粒体移植显著增加了肺组织三磷酸腺苷浓度，并改善了右心室功能，表现为血清 B 型利钠肽水平和心室直径降低。线粒体组右心室质量和壁厚度得到恢复。在接受线粒体治疗的大鼠的肺动脉中，血管平滑肌细胞表达更高水平的α-平滑肌肌动蛋白和平滑肌肌球蛋白重链 II，表明维持非增殖性、收缩表型。线粒体移植后，分离的肺动脉对α-肾上腺素能刺激的高反应性也减弱。
移植存活的线粒体可以恢复肺动脉的收缩表型和血管反应性，从而减轻已建立的肺动脉高压大鼠的后负荷和右心室重构。整体右心室功能的改善表明，线粒体移植可能成为肺动脉高压治疗的革命性临床治疗选择。
