What question did this study set out to answer?

To investigate the coordinated roles of NPPA and NPPB in cardiac function by analyzing mice deficient in these genes.

March 8, 2026Open Access

Nppa and Nppb Deficiency Drives Ventricular Hypertrophy and Subendocardial Gene Deregulation in the Mouse Heart

Key Result

Homozygous deletion of Nppa-Nppb in mice causes significant cardiac hypertrophy and subendocardial gene deregulation affecting ventricular conduction system genes.

Key Points

To investigate the coordinated roles of NPPA and NPPB in cardiac function by analyzing mice deficient in these genes.
Utilized a knockout mouse model lacking Nppa and Nppb genes.
Conducted echocardiographic assessments to evaluate heart structure and function.
Performed bulk and spatial transcriptomic analysis to assess gene expression changes.
Homozygous knockout mice exhibited significantly larger hearts and cardiomyocytic hypertrophy.
QRS prolongation was observed in electrocardiogram recordings of knockout mice.
Down-regulation of genes related to fatty acid metabolism and ventricular conduction system was identified.

Structured PICO

Population

Mice at 8 weeks of age with homozygous deletion of the Nppa-Nppb cluster (Nppa-Nppb-/-)

Intervention

Homozygous deletion of the Nppa-Nppb cluster

Comparator

Wild-type and heterozygous mice

Outcome

Cardiac phenotype including heart size, cardiomyocytic hypertrophy, and gene expressionsurrogate

Homozygous deletion of Nppa and Nppb in mice leads to cardiac hypertrophy and subendocardial gene deregulation, highlighting their essential role in cardiovascular homeostasis and ventricular conduction.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

The natriuretic peptides A and B, encoded by NPPA and NPPB, respectively, have complementary and redundant functions in cardiovascular homeostasis. To establish their coordinated roles, we analyzed the cardiac phenotype of a mouse line in which the Nppa–Nppb cluster was deleted from the genome. At 8 weeks of age, Nppa–Npbb−/−-/- mice (HOM) had significantly larger hearts and cardiomyocytic hypertrophy compared to wild-type and heterozygous mice. Electrocardiogram comparisons showed QRS prolongation in HOM mice. Hypertrophy was confirmed by echocardiography, which further indicated preservation of left ventricular systolic function. Bulk-transcriptomic analysis revealed moderate changes in gene expression of the left ventricle. Genes involved in fatty acid metabolism, ion handling and conductivity, including genes marking the ventricular conduction system, were down-regulated. Spatial transcriptomic analysis revealed the greatest changes in gene expression in the subendocardial wall, where the ventricular conduction system is located. Tbx5, the encoding dosage-sensitive T-box transcription factor Tbx5 that is essential for the expression of ventricular conduction system genes and for Nppa and Nppb, was down-regulated in the ventricles of HOM mice, indicating that a positive feedback loop normally maintains Tbx5 expression. We conclude that homozygous Nppa–Nppb deficiency in mice causes cardiac hypertrophy, including a likely perturbation of the ventricular conduction system.