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

Abstract

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: Ivana Gotic, Michael Leschnik, Ursula Kolm, Mato Markovic, Bernhard J Haubner, Katarzyna Biadasiewicz, Bernhard Metzler, Colin L Stewart, Roland Foisner
• Journal: Circulation research (Circ Res) Vol. 106 Issue 2 Pg. 346-53 (Feb 05 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 19926876 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• DNA-Binding Proteins
• Dystrophin
• GATA4 Transcription Factor
• Gata4 protein, mouse
• MEF2 Transcription Factors
• Mef2c protein, mouse
• Membrane Proteins
• Myogenic Regulatory Factors
• lamina-associated polypeptide 2
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Blotting, Western
• DNA-Binding Proteins (deficiency, genetics, physiology)
• Dystrophin (genetics, metabolism, physiology)
• Echocardiography (drug effects)
• Female
• Fibrosis
• GATA4 Transcription Factor (genetics, metabolism)
• Gene Expression Regulation, Developmental
• Heart (embryology, growth & development, physiopathology)
• Isoproterenol (pharmacology)
• MEF2 Transcription Factors
• Male
• Membrane Proteins (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Mice, Knockout
• Myocardium (metabolism, pathology)
• Myogenic Regulatory Factors (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Ventricular Dysfunction, Left (genetics, physiopathology)