Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600- Building 21111, CEP 90035-003, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500-Second floor, CEP 90050170, Porto Alegre, RS, Brazil.
Eur J Pharmacol. 2022 Jun 5;924:174950. doi: 10.1016/j.ejphar.2022.174950. Epub 2022 Apr 14.
Barth syndrome (BTHS) and dilated cardiomyopathy with ataxia syndrome (DCMA) are biochemically characterized by high levels of 3-methylglutaric acid (MGA) in the urine and plasma of affected patients. Although cardiolipin abnormalities have been observed in these disorders, their pathophysiology is not fully established. We evaluated the effects of MGA administration on redox homeostasis and mitochondrial function in heart, as well as on vascular reactivity in aorta of Wistar rats without cardiolipin genetic deficiency. Potential cardioprotective effects of a pretreatment with bezafibrate (BEZ), a pan-PPAR agonist that induces mitochondrial biogenesis, were also determined. Our findings showed that MGA induced lipid peroxidation, altered enzymatic and non-enzymatic antioxidant defenses and reduced respiratory chain function in rat heart. MGA also increased Drp1 and reduced MFN1 levels, suggesting mitochondrial fission induction. Moreover, MGA altered MAPK and Akt signaling pathways, and had a strong tendency to reduce Sirt1 and PGC-1α, indicative of mitochondrial biogenesis impairment. Aorta vascular reactivity was further altered by MGA. Additionally, BEZ mitigated most alterations on antioxidant defenses and mitochondrial quality control proteins provoked by MGA. However, vascular reactivity disturbances were not prevented. It may be presumed that oxidative stress, mitochondrial bioenergetics and control quality disturbances, and vascular reactivity impairment caused by MGA may be involved in the cardiac failure observed in BTHS and DCMA, and that BEZ should be considered as a pharmacological candidate for the treatment of these disorders.
巴特综合征 (BTHS) 和扩张型心肌病伴共济失调综合征 (DCMA) 的生化特征是患者尿液和血浆中 3-甲基戊二酸 (MGA) 水平升高。尽管这些疾病中观察到了心磷脂异常，但它们的病理生理学尚未完全确定。我们评估了 MGA 给药对未有心磷脂遗传缺陷的 Wistar 大鼠心脏氧化还原平衡和线粒体功能以及主动脉血管反应性的影响。还确定了泛 PPAR 激动剂 bezafibrate (BEZ) 预处理的潜在心脏保护作用，BEZ 可诱导线粒体生物发生。我们的研究结果表明，MGA 诱导了大鼠心脏的脂质过氧化、改变了酶和非酶抗氧化防御系统，并降低了呼吸链功能。MGA 还增加了 Drp1 并降低了 MFN1 水平，提示诱导了线粒体裂变。此外，MGA 改变了 MAPK 和 Akt 信号通路，并有强烈的趋势降低了 Sirt1 和 PGC-1α，表明线粒体生物发生受损。MGA 还进一步改变了主动脉的血管反应性。此外，BEZ 减轻了 MGA 引起的抗氧化防御和线粒体质量控制蛋白的大多数改变。然而，并未防止血管反应性的紊乱。可以假定，由 MGA 引起的氧化应激、线粒体生物能和质量控制紊乱以及血管反应性损伤可能与 BTHS 和 DCMA 中观察到的心力衰竭有关，并且 BEZ 应被视为治疗这些疾病的药物候选物。
