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首页> 外文期刊>Orphanet journal of rare diseases >The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome
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The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome

机译：PPAR全激动剂苯扎贝特可改善Barth综合征小鼠模型的心肌病

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BackgroundThe PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction. ResultsThe effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5?months of age. Bezafibrate intake over 2?months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7?months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle. ConclusionsThus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.
机译：背景技术PGC-1α/ PPAR轴已被提议作为几种代谢性疾病的潜在治疗靶标。目的是评估泛PPAR激动剂苯扎贝特对他巴欣敲除小鼠（TazKD）的疗效，他是Barth综合征的小鼠模型，表现出年龄依赖性的扩张型心肌病伴左心室（LV）功能障碍。结果苯扎贝特对心脏功能的影响通过超声心动图评估了有或没有β-肾上腺素应激的TazKD小鼠。慢性异丙肾上腺素输注引起的肾上腺素能应激会加剧TazKD小鼠的心脏表型，到4.5个月龄时显着降低左室收缩功能。摄入苯扎贝特超过2个月可明显缓解异丙肾上腺素应激的TazKD小鼠左室收缩功能障碍的发展。在没有β-肾上腺素能应激的情况下，TazKD小鼠到7个月大时会发展为扩张型心肌病。在4个月的期间内，用超药理学剂量的苯扎贝特（在啮齿类动物饮食中为0.5％）长时间治疗可有效预防小鼠异丙肾上腺素治疗中的LV扩张。苯扎贝特增加了线粒体的生物发生，但是也促进了心肌细胞的氧化应激。出人意料的是，苯扎贝特治疗小鼠的收缩功能改善同时伴有心磷脂含量的降低和心肌中单溶心磷脂水平的增加。结论因此，我们证明苯扎贝特对预防Barth综合征小鼠模型的心脏功能障碍具有有效的治疗作用，对治疗人类疾病具有明显意义。需要其他研究来评估PPAR激动剂对Barth综合征患者的潜在益处。

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