Lamina-Associated Polypeptide 2α Loss Impairs Heart Function and Stress Response in Mice

• DOI: 10.1161/circresaha.109.205724
• Publication Date: 2009-11-20T03:35:24Z
• Authors: Ivana Gotic; Michael Leschnik; Ursula Kolm; Mato Markovic; Bernhard J. Haubner; Katarzyna Biadasi...; Bernhard Metzler; Colin L. Stewart; Roland Foisner
• Keywords: MEF2C; Nuclear lamina; Cardiac Fibrosis; Conditional gene knockout; Cardiac myocyte; Knockout mouse

Lamina-associated polypeptide (LAP)2alpha is a mammalian chromatin-binding protein that interacts with fraction of A-type lamins in the nuclear interior. Because mutations and LAP2alpha lead to cardiac disorders humans, we hypothesized these factors may play important roles heart development adult tissue homeostasis.We asked whether presence was required for normal function.To study molecular mechanisms disease, analyzed structure function complete conditional Lap2alpha(-/-) mice as well Lap2alpha(-/-)/Mdx mutants. Unlike deletion late embryonic striated muscle, its knockout caused systolic dysfunction young mice, accompanied by sporadic fibrosis old animals, deregulation major transcription GATA4 myocyte enhancer factor 2c. Activation compensatory pathways, including downregulation beta-adrenergic receptor signaling, resulted reduced responsiveness myocardium chronic stimulation stalled progression LAP2alpha-deficient hearts from hypertrophy toward failure. Dystrophin deficiency an Mdx background transient rescue phenotype.Our data suggest novel role maintenance under stress conditions.