7, 8 However, the role of UTX in the regulation of aging-associated cardiac fibrosis remained unclear.Īging is associated with increased cardiac interstitial fibrosis and diastolic dysfunction. 3 A premature aging disease Hutchinson−Gilford Progeria Syndrome (HGPS) has been reported to be associated with the loss of H3K27me3. 6 Silencing of UTX-1 gene extended the mean life span of C. 5 The loss of H3K27me3 and the increased activity of the H3K27 demethylase UTX occur during aging. 3, 4 Ubiquitously transcribed tetratricopeptide repeat on X chromosome (UTX)/lysine demethylase 6A (KDM6A) is a histone demethylase enzyme responsible for removing the methyl group of histone H3 trimethylation on lysine 27 (H3K27me3)/H3K27me2 to initiate the transcription of target genes. 1, 2 The role of histone modifications in the process of aging has emerged, providing insights into epigenetic mechanisms of aging and lifespan regulation. The same results demonstrated as the in vivo study.Įpigenetic modifications play an essential role in the physiological and pathological events of organisms and contribute to the regulation of cell fate, the maintenance of cell specificity, and cell-type-specific functions. In the mechanistic study, adeno-associated virus-UTX-small hairpin RNA blocked transforming growth factor β-induced cardiac fibroblasts-to-myofibroblasts trans-differentiation in isolated fibroblasts from 24-month-old mouse heart. Silencing of UTX abolished collagen deposition and alpha smooth muscle actin activation, decreased serum transforming growth factor β, blocked cardiac fibroblasts-to-myofibroblasts trans-differentiation by elevation of cardiac resident mature fibroblast markers, TCF21, and platelet-derived growth factor receptor alpha, which are important proteins for maintaining cardiac fibroblast physiological function. Aging-associated cardiac fibrosis is characterized by fibroblast activation and abundant extracellular matrix deposition, including collagen deposition and alpha smooth muscle actin activation. Adeno-associated virus-UTX-small hairpin RNA delivery significantly attenuated aging-associated increase in blood pressure, especially in diastolic blood pressure, indicating silencing of UTX rescued aging-associated cardiac dysfunction.
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