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NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene i...

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Autores principales: Tannous, Cynthia, Deloux, Robin, Karoui, Ahmed, Mougenot, Nathalie, Burkin, Dean, Blanc, Jocelyne, Coletti, Dario, Lavery, Gareth, Li, Zhenlin, Mericskay, Mathias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036583/
https://www.ncbi.nlm.nih.gov/pubmed/33805532
http://dx.doi.org/10.3390/ijms22073534
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author Tannous, Cynthia
Deloux, Robin
Karoui, Ahmed
Mougenot, Nathalie
Burkin, Dean
Blanc, Jocelyne
Coletti, Dario
Lavery, Gareth
Li, Zhenlin
Mericskay, Mathias
author_facet Tannous, Cynthia
Deloux, Robin
Karoui, Ahmed
Mougenot, Nathalie
Burkin, Dean
Blanc, Jocelyne
Coletti, Dario
Lavery, Gareth
Li, Zhenlin
Mericskay, Mathias
author_sort Tannous, Cynthia
collection PubMed
description Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.
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spelling pubmed-80365832021-04-12 NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging Tannous, Cynthia Deloux, Robin Karoui, Ahmed Mougenot, Nathalie Burkin, Dean Blanc, Jocelyne Coletti, Dario Lavery, Gareth Li, Zhenlin Mericskay, Mathias Int J Mol Sci Article Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential. MDPI 2021-03-29 /pmc/articles/PMC8036583/ /pubmed/33805532 http://dx.doi.org/10.3390/ijms22073534 Text en © 2021 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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Tannous, Cynthia
Deloux, Robin
Karoui, Ahmed
Mougenot, Nathalie
Burkin, Dean
Blanc, Jocelyne
Coletti, Dario
Lavery, Gareth
Li, Zhenlin
Mericskay, Mathias
NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title_full NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title_fullStr NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title_full_unstemmed NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title_short NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
title_sort nmrk2 gene is upregulated in dilated cardiomyopathy and required for cardiac function and nad levels during aging
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036583/
https://www.ncbi.nlm.nih.gov/pubmed/33805532
http://dx.doi.org/10.3390/ijms22073534
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