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Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study

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Abstract

Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.

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Acknowledgements

Authors are grateful to Department of Pharmaceuticals, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, India for providing funding to carry out this research work.

Funding

Funding was received from Ministry of Chemicals and Fertilizers, Govt. of India.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali, 160062, Punjab, India

    Yogesh Bulani, Krishnamoorthy Srinivasan & Shyam Sunder Sharma

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  1. Yogesh Bulani
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  2. Krishnamoorthy Srinivasan
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  3. Shyam Sunder Sharma
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Contributions

YB performed the experiments and analysed the data. SSS conceived the study. SSS and KS were instrumental in designing the experiments and writing the manuscript.

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Correspondence to Shyam Sunder Sharma.

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Bulani, Y., Srinivasan, K. & Sharma, S.S. Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study. Mol Cell Biochem 451, 69–78 (2019). https://doi.org/10.1007/s11010-018-3394-9

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