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Suberosin Alleviates Thiazolidinedione-Induced Cardiomyopathy in Diabetic Rats by Inhibiting Ferroptosis via Modulation of ACSL4-LPCAT3 and PI3K-AKT Signaling Pathways

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Abstract

Thiazolidinediones are useful antidiabetic medications. However, their use is associated with adverse side effects like edema, heart failure and bone fractures. In this study, we investigated the anti-ferroptosis effects of suberosin (SBR; a prenylated coumarin) in diabetic Sprague Dawley rats. Further, we assessed the effects of co-administration of SBR (30 and 90 mg/kg/day) with thiazolidinedione (TZ at 15 mg/kg) to mitigate TZ-induced cardiomyopathy in diabetic rats. Our results showed that cardiac output, stroke volume, left ventricle systolic and diastolic pressures were aggravated in diabetic rats treated with TZ alone after 4 weeks. TZ treatments induced ferroptosis as well as marked histoarchitecture disarrangements in rat cardiomyocytes. The study found that optimizing volume overload alleviated cardiac hypertrophy and mitigated left ventricular dysfunction in diabetic rats co-treated with SBR. SBR co-administration with TZ reduced MDA levels in heart tissue and serum iron concentration (biomarkers of ferroptosis), downregulated mRNA expressions of LOX, ACSL4, LPCAT3, and promoted GPX4 activity as well as upregulated mRNA levels of AKT/PI3K/GSK3β as compared to the group administered with TZ at 15 mg/kg. SBR co-administration also helped to retain the normal histoarchitecture of cardiomyocytes in diabetic rats. Hence, our results suggested that SBR is an effective supplement and could be prescribed to diabetic patients along with TZ but this requires further clinical trials.

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Data Availability

The data is available upon request from the authors.

Abbreviations

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

ACSL4:

Acyl coenzyme A synthetase long-chain member 4

LOX:

Lysyl oxidase

GPX4:

Glutathione peroxidase 4

AKT:

Protein kinase B

PI3K:

Phosphoinositide 3-kinase

GSK3β:

Glycogen synthase kinase-3 beta

LVDd:

Left ventricular diastolic diameter

LVDs:

Left ventricular systolic diameter

LVEVd:

Left ventricular end-diastolic volume

LVEVs:

Left ventricular end-systolic volume

FS:

Fraction shortening

EF:

Ejection fraction

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Authors and Affiliations

  1. Department of Zoology, Government College University Faisalabad, Pakistan Government College University, Faisalabad, Pakistan

    Shabnoor Iqbal & Farhat Jabeen

  2. Pharma-Biotechnology and Traditional Medicine Center, Mbarara University of Science and Technology, Mbarara, Uganda

    Ivan Kahwa

  3. Department of Chemistry and Biochemistry, School of Sciences and Aerospace Studies, Moi University, P.O. Box 3900, Eldoret, Kenya

    Timothy Omara

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  1. Shabnoor Iqbal
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  2. Farhat Jabeen
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  4. Timothy Omara
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Contributions

SI: Investigation, writing of original draft; FJ: supervision, validation and writing; IK: data analysis; TO: review and editing.

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Correspondence to Shabnoor Iqbal.

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The animal handling and treatment experimental protocols underwent review and monitoring by the ethical committee of the Government College University, Faisalabad, Pakistan. These protocols followed the approved protocol of the European Union of animal care and Experimentation (CEE Council 86/609). The research was conducted in adherence to the ARRIVE guidelines.

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Iqbal, S., Jabeen, F., Kahwa, I. et al. Suberosin Alleviates Thiazolidinedione-Induced Cardiomyopathy in Diabetic Rats by Inhibiting Ferroptosis via Modulation of ACSL4-LPCAT3 and PI3K-AKT Signaling Pathways. Cardiovasc Toxicol 23, 295–304 (2023). https://doi.org/10.1007/s12012-023-09804-7

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