Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPK&#945;-mediated activation of RUNX2.

Chen, Jianglei; Lin, Yi; Sun, Zhongjie

Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2.

Chen, Jianglei; Lin, Yi; Sun, Zhongjie.

Afiliación

Chen J; Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Lin Y; Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Sun Z; Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Aging Cell ; 15(5): 853-60, 2016 10.

Article en En | MEDLINE | ID: mdl-27242197

RESUMEN

Fibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti-aging Klotho gene (KL) promotes high-fat-diet-induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho-deficient (KL(+/-) ) mice and WT littermates were fed with a high-fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL(+/-) mice than of WT mice, indicating that Klotho deficiency promotes HFD-induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL(+/-) mice fed with a HFD. Treatment with AICAR markedly attenuated HFD-induced AVF in KL(+/-) mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL(+/-) mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho-deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol-induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD-induced fibrosis in aortic valves, likely through the AMPKα-RUNX2 pathway.

Asunto(s)

Adenilato Quinasa/metabolismo; Envejecimiento/genética; Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo; Glucuronidasa/deficiencia; Cardiopatías Congénitas/genética; Cardiopatías Congénitas/patología; Enfermedades de las Válvulas Cardíacas/genética; Enfermedades de las Válvulas Cardíacas/patología; Animales; Válvula Aórtica/enzimología; Válvula Aórtica/patología; Enfermedad de la Válvula Aórtica Bicúspide; Colesterol/farmacología; Colágeno Tipo I/metabolismo; Dieta Alta en Grasa; Regulación hacia Abajo/efectos de los fármacos; Fibrosis; Técnicas de Silenciamiento del Gen; Glucuronidasa/genética; Cardiopatías Congénitas/enzimología; Enfermedades de las Válvulas Cardíacas/enzimología; Proteínas Klotho; Ratones; Osteocalcina/metabolismo; Sus scrofa; Regulación hacia Arriba/efectos de los fármacos

Palabras clave

AMPKα; Klotho; RUNX2; aortic valve; aortic valve interstitial cells; fibrosis

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Envejecimiento / Adenilato Quinasa / Subunidad alfa 1 del Factor de Unión al Sitio Principal / Glucuronidasa / Cardiopatías Congénitas / Enfermedades de las Válvulas Cardíacas Límite: Animals Idioma: En Revista: Aging Cell Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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