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Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction

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Abstract

Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (dp/dt max.) and minimum developed pressure (dp/dt min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat’s heart. Also, septic rat’s heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.

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Abbreviations

GSH:

Glutathione

IL-17:

Interleukin 17

IL-1β:

Interleukin 1β

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

mPTP:

Mitochondrial permeability transition pore

TNF-α:

Tumour necrosis factor α

LVEDP:

Left ventricle end-diastolic pressure

dp/dt max:

Rate of left ventricular maximum developed pressure

dp/dt min:

Rate of minimum developed pressure

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Acknowledgements

The authors thanks Mr. Parveen Garg, the Chairman of ISF College of Pharmacy, Moga for providing funding and necessary instrumentation and infrastructure facilities to carry out this research work.

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Authors and Affiliations

  1. Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India

    Pallavi Sen, Abha Kumari, Gaaminepreet Singh, Sneha Pandey & Ragini Singh

  2. Department of Pharmacy, Maharishi Markandeshwar Deemed to be University, Mullana, Ambala, Haryana, India

    Kirti Gupta

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  1. Pallavi Sen
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Contributions

PS and GS designed the study. PS and KG, AK performed all the experimental procedures and GS supervised the study. RK, AK, SP and PS helped in the preparation of manuscript. GS and KG revised the manuscript. KG helped in statistical analysis and formatting during revision of manuscript. All authors approved the final manuscript.

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Correspondence to Gaaminepreet Singh.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the department of Pharmacology, ISF College of pharmacy, Moga, (Punjab), India (ISFCP/IAEC/CPCSEA/Meeting No. 25/2019/ Protocol No. 430).

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Sen, P., Gupta, K., Kumari, A. et al. Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction. Cardiovasc Toxicol 21, 517–532 (2021). https://doi.org/10.1007/s12012-021-09643-4

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