Cardiac Muscle-Restricted Partial Loss of Nos1ap Expression Has Limited but Significant Impact on Electrocardiographic Features

Authors

Alexa Smith
Dallas Auer
Morgan Johnson
Ernesto Sanchez
Holly Ross
Christopher Ward
Aravinda Chakravarti
Ashish Kapoor

Publication Date

11-1-2023

Journal

G3

Abstract

Genome-wide association studies have identified sequence polymorphisms in a functional enhancer of the NOS1AP gene as the most common genetic regulator of QT interval and human cardiac NOS1AP gene expression in the general population. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have also demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT interval in vivo. Constitutive loss of Nos1ap led to genetic background-dependent variable lethality at or right before birth. Heart muscle-restricted Nos1ap knockout, generated using cardiac-specific alpha-myosin heavy chain promoter-driven tamoxifen-inducible Cre, resulted in tissue-level Nos1ap expression reduced by half. This partial loss of expression had no detectable effect on the QT interval or other electrocardiographic and echocardiographic parameters, except for a small but significant reduction in the QRS interval. Given that challenges associated with defining the end of the T wave on murine electrocardiogram can limit identification of subtle effects on the QT interval and that common noncoding NOS1AP variants are also associated with the QRS interval, our findings support the role of NOS1AP in regulation of the cardiac electrical cycle.

Keywords

Animals, Mice, Adaptor Proteins, Signal Transducing, Electrocardiography, Genome-Wide Association Study, Genotype, Myocardium, Polymorphism, Single Nucleotide, Zebrafish

Comments

Supplementary Materials

PMID: 37708408