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Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide

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Abstract

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.

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Acknowledgments

G. J. A. was funded by a Senior Research Fellowship from the Council of Scientific and Industrial Research, Government of India. Funding from the Department of Biotechnology, Government of India, is also gratefully acknowledged.

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Authors and Affiliations

  1. The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India

    G. Jayakumar Amirtharaj, Sathish Kumar Natarajan, Anna Pulimood, K. A. Balasubramanian & Anup Ramachandran

  2. Center for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore, 632004, India

    Aparna Venkatraman

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  1. G. Jayakumar Amirtharaj
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  2. Sathish Kumar Natarajan
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Correspondence to Anup Ramachandran.

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Amirtharaj, G.J., Natarajan, S.K., Pulimood, A. et al. Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide. Cardiovasc Toxicol 17, 175–184 (2017). https://doi.org/10.1007/s12012-016-9371-1

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