RESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Corazón/fisiopatología , Proteínas de la Membrana/fisiología , Agonistas Adrenérgicos beta/farmacología , Animales , Western Blotting , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Distrofina/genética , Distrofina/metabolismo , Distrofina/fisiología , Ecocardiografía/efectos de los fármacos , Femenino , Fibrosis , Factor de Transcripción GATA4/genética , Factor de Transcripción GATA4/metabolismo , Regulación del Desarrollo de la Expresión Génica , Corazón/embriología , Corazón/crecimiento & desarrollo , Isoproterenol/farmacología , Factores de Transcripción MEF2 , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Factores Reguladores Miogénicos/genética , Factores Reguladores Miogénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.
