Lucas Aline Maria Brito, de Lacerda Alexandre Joana Varlla, Araújo Maria Thalyne Silva, David Cicera Edna Barbosa, Ponte Viana Yuana Ivia, Coelho Beatriz Neves, Caldas Francisco Rodrigo Lemos, Varela Anna Lídia Nunes, Kowaltowski Alicia Juliana, Facundo Heberty Tarso
Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
Instituto Federal de Educação, Ciência e Tecnologia do Ceará, Juazeiro do Norte, Brazil.
Curr Mol Pharmacol. 2020;13(1):76-83. doi: 10.2174/1874467212666190723144006.
Cardiac hypertrophy involves marked wall thickening or chamber enlargement. If sustained, this condition will lead to dysfunctional mitochondria and oxidative stress. Mitochondria have ATP-sensitive K+ channels (mitoKATP) in the inner membrane that modulate the redox status of the cell.
We investigated the in vivo effects of mitoKATP opening on oxidative stress in isoproterenol- induced cardiac hypertrophy.
Cardiac hypertrophy was induced in Swiss mice treated intraperitoneally with isoproterenol (ISO - 30 mg/kg/day) for 8 days. From day 4, diazoxide (DZX - 5 mg/kg/day) was used in order to open mitoKATP (a clinically relevant therapy scheme) and 5-hydroxydecanoate (5HD - 5 mg/kg/day) or glibenclamide (GLI - 3 mg/kg/day) were used as mitoKATP blockers.
Isoproterenol-treated mice had elevated heart weight/tibia length ratios (HW/TL). Additionally, hypertrophic hearts had elevated levels of carbonylated proteins and Thiobarbituric Acid Reactive Substances (TBARS), markers of protein and lipid oxidation. In contrast, mitoKATP opening with DZX avoided ISO effects on gross hypertrophic markers (HW/TL), carbonylated proteins and TBARS, in a manner reversed by 5HD and GLI. Moreover, DZX improved mitochondrial superoxide dismutase activity. This effect was also blocked by 5HD and GLI. Additionally, ex vivo treatment of isoproterenol- induced hypertrophic cardiac tissue with DZX decreased H2O2 production in a manner sensitive to 5HD, indicating that this drug also acutely avoids oxidative stress.
Our results suggest that diazoxide blocks oxidative stress and reverses cardiac hypertrophy. This pharmacological intervention could be a potential therapeutic strategy to prevent oxidative stress associated with cardiac hypertrophy.
心肌肥大表现为明显的心肌壁增厚或心腔扩大。若这种情况持续存在，将会导致线粒体功能失调和氧化应激。线粒体的内膜上存在对ATP敏感的钾通道（mitoKATP），可调节细胞的氧化还原状态。
我们研究了mitoKATP开放对异丙肾上腺素诱导的心肌肥大氧化应激的体内影响。
对瑞士小鼠腹腔注射异丙肾上腺素（ISO - 30 mg/kg/天），持续8天以诱导心肌肥大。从第4天起，使用二氮嗪（DZX - 5 mg/kg/天）来开放mitoKATP（一种临床相关的治疗方案），并使用5 - 羟基癸酸（5HD - 5 mg/kg/天）或格列本脲（GLI - 3 mg/kg/天）作为mitoKATP阻滞剂。
经异丙肾上腺素处理的小鼠心脏重量/胫骨长度比值（HW/TL）升高。此外，肥大的心脏中蛋白质羰基化水平和硫代巴比妥酸反应性物质（TBARS）升高，这是蛋白质和脂质氧化的标志物。相比之下，用DZX开放mitoKATP可避免ISO对总体肥大标志物（HW/TL）、蛋白质羰基化和TBARS的影响，5HD和GLI可逆转这种作用。此外，DZX提高了线粒体超氧化物歧化酶活性。这种作用也被5HD和GLI阻断。另外，用DZX对异丙肾上腺素诱导的肥大心脏组织进行离体处理，以对5HD敏感的方式降低了过氧化氢的产生，表明该药物也能急性避免氧化应激。
我们的结果表明，二氮嗪可阻断氧化应激并逆转心肌肥大。这种药理学干预可能是预防与心肌肥大相关的氧化应激的潜在治疗策略。
