title: Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse.
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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne St., Cambridge, MA 02139, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Cupesi
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshioka
authors.forename: Joseph
authors.initials: J
authors.lastname: Gannon
authors.forename: Anastacia
authors.initials: A
authors.lastname: Kudinova
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D009202:Cardiomyopathies; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D010641:Phenotype; D013314:Stress, Mechanical
chemical_list: D034904:Lamin Type A; C440308:lamin C