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Updated: Mar 15, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Nppa and Nppb Deficiency Drives Ventricular Hypertrophy and Subendocardial Gene Deregulation in the Mouse Heart
Alexandra E Giovou1, Otto J Mulleners1, Marie Günthel1
1Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 1105 Amsterdam, The Netherlands.
Insights
Homozygous deletion of natriuretic peptide genes Nppa and Nppb in mice causes cardiac hypertrophy and conduction system perturbations. This study reveals a feedback loop involving Tbx5 in maintaining cardiac function.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cardiac Electrophysiology
Background:
- Natriuretic peptides A (NPPA) and B (NPPB) play crucial roles in cardiovascular homeostasis.
- Their coordinated functions and regulatory mechanisms are not fully understood.
Purpose of the Study:
- To investigate the cardiac phenotype of mice lacking the Nppa-Nppb gene cluster.
- To elucidate the role of Nppa and Nppb in cardiac development and function.
Main Methods:
- Generation and analysis of Nppa-Nppb knockout mice (HOM).
- Cardiac phenotyping including echocardiography and electrocardiography.
- Bulk and spatial transcriptomic analyses of cardiac tissue.
- Analysis of Tbx5 gene expression.
Main Results:
- Nppa-Nppb knockout mice exhibited significantly larger hearts and cardiomyocytic hypertrophy.
- Electrocardiograms revealed QRS prolongation, indicating conduction system abnormalities.
- Transcriptomic analysis showed downregulation of genes involved in fatty acid metabolism, ion handling, and the ventricular conduction system.
- Tbx5 expression was reduced in knockout mice, suggesting a disrupted feedback loop.
Conclusions:
- Homozygous Nppa-Nppb deficiency leads to cardiac hypertrophy and likely perturbs the ventricular conduction system.
- A positive feedback loop involving Tbx5 is crucial for maintaining Nppa and Nppb expression and normal cardiac function.
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-Nppb-/- 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.
