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Cardiovasc Diabetol ; 16(1): 61, 2017 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-28476142

RESUMEN

BACKGROUND: Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system. METHODS: Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks. RESULTS: WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structural abnormalities. Further, WD upregulated the expression of TRAF3IP2, a cytoplasmic adapter molecule and a regulator of multiple inflammatory mediators. Linagliptin inhibited its expression, activation of its downstream signaling intermediates NF-κB, AP-1 and p38-MAPK, and induction of multiple inflammatory mediators and growth factors that are known to contribute to development and progression of hypertrophy, fibrosis and contractile dysfunction. Linagliptin also inhibited WD-induced collagens I and III expression. Supporting these in vivo observations, linagliptin inhibited aldosterone-mediated MR-dependent oxidative stress, upregulation of TRAF3IP2, proinflammatory cytokine, and growth factor expression, and collagen induction in cultured primary cardiac fibroblasts. More importantly, linagliptin inhibited aldosterone-induced fibroblast activation and migration. CONCLUSIONS: Together, these in vivo and in vitro results suggest that inhibition of DPP-4 activity by linagliptin reverses WD-induced DD, possibly by targeting TRAF3IP2 expression and its downstream inflammatory signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cardiomiopatías/prevención & control , Dieta Occidental/efectos adversos , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Linagliptina/farmacología , Miocarditis/prevención & control , Miocardio/enzimología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Cardiomiopatías/enzimología , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Células Cultivadas , Diástole , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Fibrosis , Ratones Endogámicos C57BL , Miocarditis/enzimología , Miocarditis/etiología , Miocarditis/fisiopatología , Miocardio/ultraestructura , FN-kappa B/metabolismo , Estrés Nitrosativo/efectos de los fármacos , Obesidad/etiología , Estrés Oxidativo/efectos de los fármacos , Recuperación de la Función , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Transcripción AP-1/metabolismo , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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