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

Autor: Tannous C; Inserm Unit UMR-S 1180 CARPAT, Faculty of Pharmacy, Université Paris-Saclay, 92296 Châtenay-Malabry, France.; INSERM Unit U1164 / CNRS UMR 8256, Biologie de l'Adaptation et du Vieillissement, Institut de Biologie Paris-Seine, Sorbonne Université, 75006 Paris, France.; Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon., Deloux R; Inserm Unit UMR-S 1180 CARPAT, Faculty of Pharmacy, Université Paris-Saclay, 92296 Châtenay-Malabry, France., Karoui A; Inserm Unit UMR-S 1180 CARPAT, Faculty of Pharmacy, Université Paris-Saclay, 92296 Châtenay-Malabry, France., Mougenot N; Plateau d'Expérimentation Cœur, Muscle, Vaisseaux PECMV, UMS28, Sorbonne Université, 75013 Paris, France., Burkin D; Department of Pharmacology, Reno School of Medicine, University of Nevada, Reno, NV 89102, USA., Blanc J; INSERM Unit U1164 / CNRS UMR 8256, Biologie de l'Adaptation et du Vieillissement, Institut de Biologie Paris-Seine, Sorbonne Université, 75006 Paris, France., Coletti D; INSERM Unit U1164 / CNRS UMR 8256, Biologie de l'Adaptation et du Vieillissement, Institut de Biologie Paris-Seine, Sorbonne Université, 75006 Paris, France., Lavery G; Institute of Metabolism and Systems Research, University of Birmingham, 2nd Floor IBR Tower, Edgbaston, Birmingham B15 2TT, UK., Li Z; INSERM Unit U1164 / CNRS UMR 8256, Biologie de l'Adaptation et du Vieillissement, Institut de Biologie Paris-Seine, Sorbonne Université, 75006 Paris, France., Mericskay M; Inserm Unit UMR-S 1180 CARPAT, Faculty of Pharmacy, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Mar 29; Vol. 22 (7). Date of Electronic Publication: 2021 Mar 29.
DOI: 10.3390/ijms22073534
Abstrakt: 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.
Databáze: MEDLINE
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