Antioxidant system disturbances and mitochondrial dysfunction induced by 3-methyglutaric acid in rat heart are prevented by bezafibrate

内科学 心磷脂 内分泌学 线粒体 氧化应激 线粒体生物发生 脂质过氧化 生物 化学 医学 生物化学 磷脂
作者
Nevton Teixeira da Rosa-Junior,Belisa Parmeggiani,Nícolas Manzke Glänzel,Leonardo de Moura Alvorcem,Morgana Brondani,Renata Lopes Britto,Mateus Grings,Vanessa Duarte Ortiz,Patrick Türck,Alex Sander da Rosa Araújo,Moaçir Wajner,Guilhian Leipnitz
出处
期刊:European Journal of Pharmacology [Elsevier]
卷期号:924: 174950-174950 被引量:4
标识
DOI:10.1016/j.ejphar.2022.174950
摘要

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.
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