Asunto(s)
Enfermedades del Aparato Lagrimal/complicaciones , Litiasis/complicaciones , Conducto Nasolagrimal/patología , Adulto , Anciano , Femenino , Humanos , Enfermedades del Aparato Lagrimal/diagnóstico , Enfermedades del Aparato Lagrimal/cirugía , Litiasis/diagnóstico , Litiasis/cirugía , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: In heart failure (HF), ventricular myocardium expresses brain natriuretic peptide (BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis. METHODS AND RESULTS: We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% (n=8) compared with unloaded preparations (n=8; P<0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients (350 pg/mL) abolished SERCA upregulation by stretch (n=9; P<0.0001 versus BNP free). Inhibition of cyclic guanosine 3',5' monophosphate (cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation (n=15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP. CONCLUSIONS: Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.
Asunto(s)
ATPasas Transportadoras de Calcio/biosíntesis , Insuficiencia Cardíaca/fisiopatología , Péptido Natriurético Encefálico/fisiología , Retículo Sarcoplasmático/enzimología , 3',5'-GMP Cíclico Fosfodiesterasas/fisiología , Adulto , Animales , Calcineurina/fisiología , Señalización del Calcio , ATPasas Transportadoras de Calcio/genética , Cardiomiopatía Dilatada/complicaciones , Estudios de Cohortes , GMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Inducción Enzimática/efectos de los fármacos , Femenino , Guanilato Ciclasa/fisiología , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Miocardio/enzimología , Factores de Transcripción NFATC/fisiología , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/farmacología , ARN Mensajero/biosíntesis , Receptores del Factor Natriurético Atrial/fisiología , Proteínas Recombinantes de Fusión/farmacología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Estrés MecánicoRESUMEN
The present study investigated the effect of tumor necrosis factor (TNF)-alpha on myocardial energy metabolism as estimated by myocardial oxygen consumption (MVo(2)). MVo(2) of electrically stimulated isolated trabeculae of right ventricular Wistar rat myocardium was analyzed using a Clark-type oxygen probe. After the initial data collection in the absence of TNF-alpha, measurements were repeated after TNF-alpha stimulation. In separate experiments, pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) or the ceramidase inhibitor n-oleoylethanolamine (NOE) was done to investigate NO/sphingosine-related effects. TNF-alpha impaired myocardial economy at increasing stimulation frequencies without altering baseline MVo(2). Incubation with TNF-alpha in the presence of l-NAME further impaired myocardial economy. NOE preincubation abrogated the TNF-alpha effect on myocardial economy. Moreover, the negative inotropic effect of TNF-alpha was observed in NOE-pretreated but not l-NAME-pretreated muscle fibers. Exogenous sphingosine mimicked the TNF-alpha effect on mechanics and energetics. We conclude that TNF-alpha impairs the economy of chemomechanical energy transduction primarily through a sphingosine-mediated pathway.