Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse
- 16 November 2009
- journal article
- research article
- Published by Elsevier BV in Journal of Molecular and Cellular Cardiology
- Vol. 48 (6), 1290-1297
- https://doi.org/10.1016/j.yjmcc.2009.10.024
Abstract
Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna−/− mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna+/− mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna+/− mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna+/− animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna+/− mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart.Keywords
Funding Information
- National Institutes of Health (R01 HL082792, R01 NS059348)
- American Heart Association (0635359N, 0835484N)
This publication has 57 references indexed in Scilit:
- Intermediate filaments: primary determinants of cell architecture and plasticityJCI Insight, 2009
- Laminopathies and the long strange trip from basic cell biology to therapyJCI Insight, 2009
- Dysfunctional Connections Between the Nucleus and the Actin and Microtubule Networks in Laminopathic ModelsBiophysical Journal, 2008
- Reduced expression of A-type lamins and emerin activates extracellular signal-regulated kinase in cultured cellsBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2008
- Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type laminsHuman Molecular Genetics, 2008
- Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system diseaseJournal of Molecular and Cellular Cardiology, 2008
- Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophyJCI Insight, 2007
- SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the CytoskeletonMolecular and Cellular Biology, 2006
- The Stability of the Nuclear Lamina Polymer Changes with the Composition of Lamin Subtypes According to Their Individual Binding StrengthsPublished by Elsevier BV ,2004
- Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-System DiseaseNew England Journal of Medicine, 1999