Lamina-associated polypeptide 2α loss impairs heart function and stress response in mice

Abstract

Rationale: Lamina-associated polypeptide (LAP)2α is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2α lead to cardiac disorders in humans, we hypothesized that these factors may play important roles in heart development and adult tissue homeostasis. Objective: We asked whether the presence of LAP2α was required for normal cardiac function. Methods and Results: To study the molecular mechanisms of the disease, we analyzed heart structure and function in complete and conditional Lap2α-/- mice as well as Lap2α-/-/Mdx mutants. Unlike conditional deletion of LAP2α in late embryonic striated muscle, its complete knockout caused systolic dysfunction in young mice, accompanied by sporadic fibrosis in old animals, as well as deregulation of major cardiac transcription factors GATA4 and myocyte enhancer factor 2c. Activation of compensatory pathways, including downregulation of β-adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic β-adrenergic stimulation and stalled the progression of LAP2α-deficient hearts from hypertrophy toward cardiac failure. Dystrophin deficiency in an Mdx background resulted in a transient rescue of the Lap2α-/- phenotype. Conclusions: Our data suggest a novel role of LAP2α in the maintenance of cardiac function under normal and stress conditions. © 2010 American Heart Association, Inc.