Amirtharaj G Jayakumar, Natarajan Sathish Kumar, Pulimood Anna, Balasubramanian K A, Venkatraman Aparna, Ramachandran Anup
The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India.
Center for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore, 632004, India.
Cardiovasc Toxicol. 2017 Apr;17(2):175-184. doi: 10.1007/s12012-016-9371-1.
Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.
硫代乙酰胺（TAA）给药被广泛用于诱导大鼠肝硬化，其中活性氧自由基（ROS）和一氧化氮（NO）参与肝损伤的发展。心脏功能障碍是肝硬化的重要并发症，但ROS或NO在肝硬化期间心脏异常中的作用尚未完全明确。本研究在TAA诱导的肝硬化动物中进行，评估了心脏氧化应激、NO和线粒体功能的时间变化。在明显肝硬化形成之前，TAA诱导心脏中硝酸盐水平升高，且无明显组织学改变。这伴随着P38丝裂原活化蛋白激酶的早期诱导，P38丝裂原活化蛋白激酶受ROS影响，对诱导诱导型一氧化氮合酶起重要信号作用。在明显肝硬化形成之前，心脏和心脏线粒体中硝基酪氨酸增加、蛋白质氧化和脂质过氧化增加，提示存在氧化应激。然而，当肝硬化明显时，后期出现心脏线粒体功能受损，呼吸控制率降低和线粒体肿胀增加。总之，TAA诱导心脏中ROS和NO升高，与早期肝损伤平行。这导致肝硬化形成后心脏线粒体功能缺陷的后期发展。
