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Melatonin Attenuates Extracellular Matrix Accumulation and Cardiac Injury Manifested by Copper

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Abstract

Copper-induced cardiac injury is not widely reported in spite of its ability to cause oxidative damage and tissue injury. Structural and morphological changes in the cardiac tissue are triggered via oxidative stress and inflammatory responses following copper exposure. The varied and unavoidable exposure of copper through contaminated food and water warrants a safe and effective agent against its harmful effects. Since the heart is highly sensitive to changes in the redox balance, the present study was undertaken to examine the protective effects of melatonin against copper-induced cardiac injury. Sprague Dawley (SD) rats were exposed to 100 ppm of elemental copper via drinking water for 4 months. The cardiac tissue was evaluated for various biochemical, histological, and protein expression studies. Animals exposed to copper exhibited induced oxidative stress and cardiac injury compared to normal control. To this end, we found that melatonin treatment ameliorated copper-induced alterations in tissue oxidative variables like ROS, nitrate, MDA, and GSH. In addition, histological examinations unravelled decreased cardiac muscle dilation, atrophy, and cardiomyopathy in melatonin-treated rats. Furthermore, melatonin-treated rats were associated with reduced tissue copper levels, collagen deposition, α-SMA, and increased HO-1 expression as compared to rats exposed exclusively to copper. Moreover, the levels of NF-κB and cardiac markers such as CK-MB, cTnI, and cTnT were found to be decreased in the melatonin-treated animals. Altogether, melatonin-triggered increase in antioxidant capacity resulting in reduced aggregation of ECM components demonstrates the therapeutic potential of melatonin in the treatment of cardiac injury and tissue fibrosis.

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Abbreviations

α-SMA:

Alpha smooth muscle actin

CK-MB:

Creatinine kinase-MB

Cu:

Copper

CuSO4·5H2O:

Copper(II) sulfate pentahydrate

CVDs:

Cardiovascular diseases

ECM:

Extracellular matrix

ELISA:

Enzyme-linked immunosorbent assay

GSH:

Reduced glutathione

H & E:

Hematoxylin and eosin

HO-I:

Heam oxygenase-I

IHC:

Immunohistochemistry

I.P.:

Intraperitoneal

M:

Melatonin

MT:

Masson’s trichrome

NC:

Normal control

NF-κB:

Nuclear factor kappa B

PBS:

Phosphate-buffered saline

PSR:

Picrosirius red, ROS: reactive oxygen species

SEM:

Standard error of mean

cTnI:

Troponin-I

cTnT:

Troponin-T

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Acknowledgements

The authors would like to thank the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, and the Director, NIPER-Raebareli, for providing the financial aid and resources.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, 226002, India

    Syed Afroz Ali, Sumadhura ‬‬‬‬‬‬‬Bommaraju, Jayant Patwa & Ashok Kumar Datusalia

  2. Crop Production and Protection Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India

    Puja Khare

  3. Department of Biology, University of Saskatchewan, Saskatoon, Canada

    Mahesh Rachamalla & Som Niyogi

  4. Toxicology Centre, University of Saskatchewan, Saskatoon, Canada

    Som Niyogi

  5. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, 226002, India

    Ashok Kumar Datusalia

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  1. Syed Afroz Ali
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Contributions

SAA: conceptualization, performed all the experiments, analyzed the data, prepared and edited the original draft. SB and JP: conceptualization and performed animal experiments. PK: performed metal estimation. MR and SN: conceptualization, review and edited the final draft. AKD: conceptualization, supervision, project administration, resources, funding acquisition, review and edited the final draft.

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Correspondence to Ashok Kumar Datusalia.

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All the experiments on animals were approved by the Institutional Animal Ethics Committee (protocol no: NIPER/RBL/IAEC/84/Dec 2021) and as per the accordance of CPCSEA, Govt of India.

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Ali, S.A., ‬‬‬‬‬‬‬Bommaraju, S., Patwa, J. et al. Melatonin Attenuates Extracellular Matrix Accumulation and Cardiac Injury Manifested by Copper. Biol Trace Elem Res 201, 4456–4471 (2023). https://doi.org/10.1007/s12011-022-03509-8

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