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Cyclosporine A induces cardiac remodeling through TGF-β/Smad3/miR-29 signaling pathway and alters gene expression of miR-30b-5p/CaMKIIδ isoforms pathways: alleviating effects of moderate exercise

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Abstract

Background

Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy are highly known phenomena; however, the basic mechanisms of CsA cardiotoxicity are unclear. The present study evaluated the role of the Transforming growth factor-beta (TGF-β)/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under CsA exposure alone or combined with moderate exercise.

Methods

A total of 24 male Wistar rats were divided into control, cyclosporine (30 mg/kg BW), and cyclosporine-exercise groups.

Results

After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression and an increase in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteinases (MMPs), protein expression of TGF-β, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), and plasma LDL and cholesterol levels in the CsA-treated group compared to the control group. The CsA group presented greater histological heart changes such as fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/heart weight than the control group. Moreover, combined moderate exercise and CsA relatively improved gene expression changes and histological alternations compared to the CsA group.

Conclusion

TGF-β-Smad3-miR-29 and CaMKIIδ isoforms may mainly contribute to the progression of heart fibrosis and hypertrophy due to CsA exposure, providing new insight into the pathogenesis and treatment of CsA-induced side effects on the heart tissue.

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Data Availability

The data that support the finding of this study are available from the corresponding author upon reasonable request.

Abbreviations

TGF-β:

Transforming growth factor-beta

CaMKII:

Calcium/calmodulin-dependent protein kinase II

CsA:

Cyclosporine

MMPs:

Matrix Metalloproteins

Ox-LDL:

Oxidase-low-density lipoprotein

ROS:

Reactive oxygen species

PVDF:

Polyvinylidene Fluoride

OS:

Oxidative Stress

SD:

Smad-dependent

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran

    Khatereh Nourmohammadi & Roya Naderi

  2. Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran

    Abolfazl Bayrami & Alireza Shirpoor

  3. Nephrology and Kidney Transplant Research Center, Clinical research institute, Urmia University of Medical Sciences, Urmia, Iran

    Roya Naderi & Alireza Shirpoor

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  1. Khatereh Nourmohammadi
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Contributions

Khatereh nourmohammadi: Conceptualization, Methodology, Software abolfazl bayrami.: Data curation, Writing- Original draft preparation. Roya naderi: Visualization, Investigation. Alireza shirpoor: Supervision. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Alireza Shirpoor.

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the Local Ethics Committee on Animal Experiments at Mohaghegh Ardabili University in Iran confirmed this study (IR.UMA.REC.1400.032).

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Nourmohammadi, K., Bayrami, A., Naderi, R. et al. Cyclosporine A induces cardiac remodeling through TGF-β/Smad3/miR-29 signaling pathway and alters gene expression of miR-30b-5p/CaMKIIδ isoforms pathways: alleviating effects of moderate exercise. Mol Biol Rep 50, 5859–5870 (2023). https://doi.org/10.1007/s11033-023-08506-1

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