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1.
Circulation ; 145(11): 829-846, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35235343

RESUMEN

BACKGROUND: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. METHODS: We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. RESULTS: We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. CONCLUSIONS: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.


Asunto(s)
Insuficiencia Cardíaca , Función Ventricular Izquierda , Animales , Cardiomegalia/metabolismo , Metabolismo Energético , Insuficiencia Cardíaca/etiología , Humanos , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Volumen Sistólico , Quinasas DyrK
2.
Fitoterapia ; 73(1): 95-6, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11864769

RESUMEN

A novel acylated flavonol glycoside, quercetin 3-O-[2' "-O-(E)-caffeoyl]-alpha-L-arabinopyranosyl-(1-->6)-beta-D-galactopyranoside (1), was isolated from whole plant of Morina nepalensis var. alba. Its structure was determined on the basis of chemical and spectroscopic methods.


Asunto(s)
Flavonoides/química , Glicósidos/química , Magnoliopsida , Fitoterapia , Extractos Vegetales/química , Flavonoides/aislamiento & purificación , Flavonoles , Glicósidos/aislamiento & purificación , Humanos , Espectroscopía de Resonancia Magnética , Extractos Vegetales/aislamiento & purificación
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