Nkx2-5 Loss of Function in the His-Purkinje System Hampers Its Maturation and Leads to Mechanical Dysfunction.

Autor:	Choquet C; Aix-Marseille Univ, CNRS UMR 7288, IBDM, 13288 Marseille, France; Aix-Marseille Univ, INSERM, MMG, 13385 Marseille, France, Sicard P; INSERM, CNRS, Université de Montpellier, PHYMEDEXP, 34295 Montpellier, France, Vahdat J; Aix-Marseille Univ, CNRS UMR 7288, IBDM, 13288 Marseille, France, Nguyen THM; Aix-Marseille Univ, CNRS UMR 7288, IBDM, 13288 Marseille, France; Aix-Marseille Univ, INSERM UMR 1090, TAGC, 13288 Marseille, France; Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi 10072, Vietnam, Kober F; Aix-Marseille Univ, CNRS, CRMBM, 13385 Marseille, France, Varlet I; Aix-Marseille Univ, CNRS, CRMBM, 13385 Marseille, France, Bernard M; Aix-Marseille Univ, CNRS, CRMBM, 13385 Marseille, France, Richard S; INSERM, CNRS, Université de Montpellier, PHYMEDEXP, 34295 Montpellier, France, Kelly RG; Aix-Marseille Univ, CNRS UMR 7288, IBDM, 13288 Marseille, France, Lalevée N; Aix-Marseille Univ, INSERM UMR 1090, TAGC, 13288 Marseille, France; Aix-Marseille Univ, INSERM UMR 1263, C2VN, 13005 Marseille, France, Miquerol L; Aix-Marseille Univ, CNRS UMR 7288, IBDM, 13288 Marseille, France
Jazyk:	angličtina
Zdroj:	Journal of cardiovascular development and disease [J Cardiovasc Dev Dis] 2023 Apr 27; Vol. 10 (5). Date of Electronic Publication: 2023 Apr 27.
DOI:	10.3390/jcdd10050194
Abstrakt:	The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40 -positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5 -deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR' complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.
Databáze:	MEDLINE
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