RATIONALE: Lamina-associated polypeptide (LAP)2alpha is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2alpha 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 LAP2alpha 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 Lap2alpha(-/-) mice as well as Lap2alpha(-/-)/Mdx mutants. Unlike conditional deletion of LAP2alpha 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 beta-adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic beta-adrenergic stimulation and stalled the progression of LAP2alpha-deficient hearts from hypertrophy toward cardiac failure. Dystrophin deficiency in an Mdx background resulted in a transient rescue of the Lap2alpha(-/-) phenotype. CONCLUSIONS: Our data suggest a novel role of LAP2alpha in the maintenance of cardiac function under normal and stress conditions.
RATIONALE: Lamina-associated polypeptide (LAP)2alpha is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2alpha 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 LAP2alpha 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 Lap2alpha(-/-) mice as well as Lap2alpha(-/-)/Mdx mutants. Unlike conditional deletion of LAP2alpha 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 beta-adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic beta-adrenergic stimulation and stalled the progression of LAP2alpha-deficient hearts from hypertrophy toward cardiac failure. Dystrophin deficiency in an Mdx background resulted in a transient rescue of the Lap2alpha(-/-) phenotype. CONCLUSIONS: Our data suggest a novel role of LAP2alpha in the maintenance of cardiac function under normal and stress conditions.
Authors: Nana Naetar; Barbara Korbei; Serguei Kozlov; Marc A Kerenyi; Daniela Dorner; Rosana Kral; Ivana Gotic; Peter Fuchs; Tatiana V Cohen; Reginald Bittner; Colin L Stewart; Roland Foisner Journal: Nat Cell Biol Date: 2008-10-12 Impact factor: 28.824
Authors: Ji-Yeon Shin; Caroline Le Dour; Fusako Sera; Shinichi Iwata; Shunichi Homma; Leroy C Joseph; John P Morrow; William T Dauer; Howard J Worman Journal: Nucleus Date: 2014-05-23 Impact factor: 4.197