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Catalase inhibition in diabetic rats potentiates DNA damage and apoptotic cell death setting the stage for cardiomyopathy

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Abstract

Diabetes is a risk factor for cardiovascular disease that has a multifactorial etiology, with oxidative stress as an important component. Our previous observation of a significant diabetes-related increase in rat cardiac catalase (CAT) activity suggested that CAT could play a major role in delaying the development of diabetic cardiomyopathy. Thus, in the present work, we examined the effects of the daily administration of the CAT inhibitor, 3-amino-1,2,4-triazole (1 mg/g), on the hearts of streptozotocin (STZ)-induced diabetic rats. Administration of CAT inhibitor was started from the 15th day after the last STZ treatment (40 mg/kg/5 days), and maintained until the end of the 4th or 6th weeks of diabetes. Compared to untreated diabetic rats, at the end of the observation period, CAT inhibition lowered the induced level of cardiac CAT activity to the basal level and decreased CAT protein expression, mediated through a decline in the nuclear factor erythroid-derived 2-like 2 /nuclear factor-kappa B p65 (Nrf2/NF-κB p65) subunit ratio. The perturbed antioxidant defenses resulting from CAT inhibition promoted increased H2O2 production (P < 0.05) and lipid peroxidation (P < 0.05). Generated cytotoxic stimuli increased DNA damage (P < 0.05) and activated pro-apoptotic events, observed as a decrease (P < 0.05) in the ratio of the apoptosis regulator proteins Bcl-2/Bax, increased (P < 0.05) presence of the poly(ADP-ribose) polymerase-1 (PARP-1) 85 kDa apoptotic fragment and cytoplasmic levels of cytochrome C. These findings confirm an important function of CAT in the suppression of events leading to diabetes-promoted cardiac dysfunction and cardiomyopathy.

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Acknowledgments

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. 173020).

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Authors and Affiliations

  1. Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11060, Serbia

    Svetlana Ivanović-Matić, Desanka Bogojević, Vesna Martinović, Anja Petrović, Sofija Jovanović-Stojanov, Goran Poznanović & Ilijana Grigorov

  2. Institute for Biological Research “Siniša Stanković”, Bulevar despota Stefana 142, Belgrade, 11060, Serbia

    Svetlana Ivanović-Matić

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  1. Svetlana Ivanović-Matić
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Correspondence to Svetlana Ivanović-Matić.

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Ivanović-Matić, S., Bogojević, D., Martinović, V. et al. Catalase inhibition in diabetic rats potentiates DNA damage and apoptotic cell death setting the stage for cardiomyopathy. J Physiol Biochem 70, 947–959 (2014). https://doi.org/10.1007/s13105-014-0363-y

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