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PBX/Knotted 1 homeobox-2(PKNOX2)is a novel regulator of myocardial fibrosis

Signal Transduction and Targeted Therapy 2024年第5期9卷 2231-2249页

作者： Liang Chen Haotong Li Xiaorui Liu Ningning Zhang Kui Wang Anteng Shi Hang Gao deniz akdis Ardan MSaguner Xinjie Xu Elena Osto Willem Van de Veen Guangyu Li Antoni Bayés-Genís Firat Duru Jiangping Song Xiangjie Li Shengshou Hu State Key Laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R.China School of Statistics and Data Science Nankai UniversityTianjinChina Department of Cardiology University Heart CenterUniversity Hospital Zurich and University of ZurichZurichSwitzerland Institute for Clinical Chemistry University Hospital Zurich and University of ZürichZurichSwitzerland Swiss Institute of Allergy and Asthma Research(SIAF) University of ZurichDavosSwitzerland Heart Institute Hospital Universitari Germans Trias i PujolBadalonaCIBERCVSpain

Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA ***,the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription *** this study,we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription *** this unbiased protocol,we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell *** in fibroblasts,a novel regulator,PKNOX2,was identified as being associated with physiological fibroblast activation in healthy *** validate the roles of these transcription factors in maintaining homeostasis,we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast *** trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast *** gain-and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis ***,fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis,*** summary,this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart *** this optimized protocol,we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

关键词： NOX2 homeostasis fibrosis

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