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1.
Braz. j. med. biol. res ; 52(1): e7914, 2019. graf
Artículo en Inglés | LILACS | ID: biblio-974273

RESUMEN

Yes-associated protein (YAP) is an important regulator of cellular proliferation and transdifferentiation. However, little is known about the mechanisms underlying myofibroblast transdifferentiation in dilated cardiomyopathy (DCM). We investigated the role of YAP in the pathological process of cardiac matrix remodeling. A classic model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Cardiac fibroblasts were isolated from neonatal Sprague-Dawley rats by density gradient centrifugation. The expression levels of α-smooth muscle actin (α-SMA) and collagen volume fraction (CVF) were significantly increased in DCM mice. Angiotensin II (Ang II)-mediated YAP activation promoted the proliferation and transdifferentiation of neonatal rat cardiac fibroblasts, and this effect was significantly suppressed in the shRNA YAP + Ang II group compared with the shRNA Control + Ang II group in vitro (2.98±0.34 ×105 vs 5.52±0.82 ×105, P<0.01). Inhibition of endogenous Ang II-stimulated YAP improved the cardiac function by targeting myofibroblast transdifferentiation to attenuate matrix remodeling in vivo. In the valsartan group, left ventricular ejection fraction and fractional shortening were significantly increased compared with the DCM group (52.72±5.51% vs 44.46±3.01%, P<0.05; 34.84±3.85% vs 26.65±3.12%, P<0.01). Our study demonstrated that YAP was a regulator of cardiac myofibroblast differentiation, and regulation of YAP signaling pathway contributed to improve cardiac function of DCM mice, possibly in part by decreasing myofibroblast transdifferentiation to inhibit matrix remodeling.


Asunto(s)
Animales , Masculino , Ratas , Angiotensina II/farmacología , Cardiomiopatía Dilatada/fisiopatología , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Transdiferenciación Celular/efectos de los fármacos , Miofibroblastos/efectos de los fármacos , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/fisiología , Porcinos , Ecocardiografía , Cardiomiopatía Dilatada/patología , Diferenciación Celular , Western Blotting , Ratas Sprague-Dawley , Proteínas de Ciclo Celular , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/fisiología , Modelos Animales de Enfermedad , Miofibroblastos/fisiología , Ratones Endogámicos BALB C , Microscopía Fluorescente
2.
Braz. j. med. biol. res ; 40(5): 679-686, May 2007. ilus, graf, tab
Artículo en Inglés | LILACS | ID: lil-449077

RESUMEN

Insulin receptor substrate-1 (IRS-1) is the main intracellular substrate for both insulin and insulin-like growth factor I (IGF-I) receptors and is critical for cell mitogenesis. Thyrotropin is able to induce thyroid cell proliferation through the cyclic AMP intracellular cascade; however, the presence of either insulin or IGF-I is required for the mitogenic effect of thyroid-stimulating hormone (TSH) to occur. The aim of the present study was to determine whether thyroid IRS-1 content is modulated by TSH in vivo. Strikingly, hypothyroid goitrous rats, which have chronically high serum TSH levels (control, C = 2.31 ± 0.28; methimazole (MMI) 21d = 51.02 ± 6.02 ng/mL, N = 12 rats), when treated with 0.03 percent MMI in drinking water for 21 days, showed significantly reduced thyroid IRS-1 mRNA content. Since goiter was already established in these animals by MMI for 21 days, we also evaluated IRS-1 expression during goitrogenesis. Animals treated with MMI for different periods of time showed a progressive increase in thyroid weight (C = 22.18 ± 1.21; MMI 5d = 32.83 ± 1.48; MMI 7d = 31.1 ± 3.25; MMI 10d = 33.8 ± 1.25; MMI 14d = 45.5 ± 2.56; MMI 18d = 53.0 ± 3.01; MMI 21d = 61.9 ± 3.92 mg, N = 9-15 animals per group) and serum TSH levels (C = 1.57 ± 0.2; MMI 5d = 9.95 ± 0.74; MMI 7d = 10.38 ± 0.84; MMI 10d = 17.72 ± 1.47; MMI 14d = 25.65 ± 1.23; MMI 18d = 35.38 ± 3.69; MMI 21d = 31.3 ± 2.7 ng/mL, N = 9-15 animals per group). Thyroid IRS-1 mRNA expression increased progressively during goitrogenesis, being significantly higher by the 14th day of MMI treatment, and then started to decline, reaching the lowest values by the 21st day, when a significant reduction was detected. In the liver of these animals, however, a significant decrease of IRS-1 mRNA was detected after 14 days of MMI treatment, a mechanism probably involved in the insulin resistance that occurs in hypothyroidism. The increase in IRS-1 expression during goitrogenesis may represent...


Asunto(s)
Animales , Masculino , Ratas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Bocio/metabolismo , Hipotiroidismo/metabolismo , Glándula Tiroides/citología , Tirotropina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Bocio/inducido químicamente , Hipotiroidismo/inducido químicamente , Mitosis , Metimazol/farmacología , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ARN Mensajero/análisis , Glándula Tiroides/efectos de los fármacos , Tirotropina/efectos de los fármacos
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