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Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP...

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Autores principales: Dawood, Amal F., Alzamil, Norah M., Hewett, Peter W., Momenah, Maha A., Dallak, Mohammad, Kamar, Samaa S., Abdel Kader, Dina H., Yassin, Hanaa, Haidara, Mohamed A., Maarouf, Amro, Al-Ani, Bahjat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139128/
https://www.ncbi.nlm.nih.gov/pubmed/35625721
http://dx.doi.org/10.3390/biomedicines10050984
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author Dawood, Amal F.
Alzamil, Norah M.
Hewett, Peter W.
Momenah, Maha A.
Dallak, Mohammad
Kamar, Samaa S.
Abdel Kader, Dina H.
Yassin, Hanaa
Haidara, Mohamed A.
Maarouf, Amro
Al-Ani, Bahjat
author_facet Dawood, Amal F.
Alzamil, Norah M.
Hewett, Peter W.
Momenah, Maha A.
Dallak, Mohammad
Kamar, Samaa S.
Abdel Kader, Dina H.
Yassin, Hanaa
Haidara, Mohamed A.
Maarouf, Amro
Al-Ani, Bahjat
author_sort Dawood, Amal F.
collection PubMed
description The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.
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spelling pubmed-91391282022-05-28 Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis Dawood, Amal F. Alzamil, Norah M. Hewett, Peter W. Momenah, Maha A. Dallak, Mohammad Kamar, Samaa S. Abdel Kader, Dina H. Yassin, Hanaa Haidara, Mohamed A. Maarouf, Amro Al-Ani, Bahjat Biomedicines Article The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects. MDPI 2022-04-23 /pmc/articles/PMC9139128/ /pubmed/35625721 http://dx.doi.org/10.3390/biomedicines10050984 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dawood, Amal F.
Alzamil, Norah M.
Hewett, Peter W.
Momenah, Maha A.
Dallak, Mohammad
Kamar, Samaa S.
Abdel Kader, Dina H.
Yassin, Hanaa
Haidara, Mohamed A.
Maarouf, Amro
Al-Ani, Bahjat
Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title_full Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title_fullStr Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title_full_unstemmed Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title_short Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
title_sort metformin protects against diabetic cardiomyopathy: an association between desmin–sarcomere injury and the inos/mtor/timp-1 fibrosis axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139128/
https://www.ncbi.nlm.nih.gov/pubmed/35625721
http://dx.doi.org/10.3390/biomedicines10050984
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