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

Zhenlin Li,Gareth Lavery,Dean Burkin,Mathias Mericskay,Robin Deloux,Cynthia Tannous,Jocelyne Blanc,Dario Coletti,Nathalie Mougenot,Ahmed Karoui

doi:10.3390/ijms22073534

Abstract

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.

Highlights

Dilated Cardiomyopathy (DCM) is a severe heart disease characterized by the dilation of the left and right ventricles leading to a systolic dysfunction and reduced ejection fraction, without hypertension, pressure overload or coronary artery disease sufficient to cause global systolic impairment [1]
The expression of cardiac genes encoding sarcomeric proteins, cytoskeleton linkers and receptors, such as the integrin receptors and dystrophinglycoprotein complex connected to the extracellular matrix (ECM) [5,6], as well as genes involved in the regulation of energy metabolism are commonly perturbated in DCM [7]
We identified a gene with two different annotations in different databases, integrin β1 binding protein 3 (Itgb1bp3) or nicotinamide riboside kinase 2 (Nmrk2, official symbol), as a robustly upregulated in several etiologically distinct mouse models of DCM [8,9]

Summary

Introduction

Dilated Cardiomyopathy (DCM) is a severe heart disease characterized by the dilation of the left and right ventricles leading to a systolic dysfunction and reduced ejection fraction, without hypertension, pressure overload or coronary artery disease sufficient to cause global systolic impairment [1]. Mutations in 30 genes encoding mostly but not exclusively cytoskeletal proteins, have been identified in monogenic forms of DCM though modern high-throughput genome sequencing approaches, suggesting that multiple gene variants may be involved in some cases [1,3]. An appealing alternative approach is to identify therapeutic targets that will be common to DCM with different etiologies to target the largest number of patients. We identified a gene with two different annotations in different databases, integrin β1 binding protein 3 (Itgb1bp3) or nicotinamide riboside kinase 2 (Nmrk, official symbol), as a robustly upregulated in several etiologically distinct mouse models of DCM [8,9]

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