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

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 

机构地区：[1]State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,P.R.China [2]School of Statistics and Data Science,Nankai University,Tianjin,China [3]Department of Cardiology,University Heart Center,University Hospital Zurich and University of Zurich,Zurich,Switzerland [4]Institute for Clinical Chemistry,University Hospital Zurich and University of Zürich,Zurich,Switzerland [5]Swiss Institute of Allergy and Asthma Research(SIAF),University of Zurich,Davos,Switzerland [6]Heart Institute,Hospital Universitari Germans Trias i Pujol,Badalona,CIBERCV,Spain

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期2231-2249,共19页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(82100377);National High Level Hospital Clinical Research Funding(2023-GSP-RC-01,2023-GSP-ZD-2);the Beijing Nova Program(Z211100002121046,20220484205).Figure 10 was created with BioRender.com.

摘　　要：Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing.However,the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors.In 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 factors.With 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 subtypes.Particularly in fibroblasts,a novel regulator,PKNOX2,was identified as being associated with physiological fibroblast activation in healthy hearts.To validate the roles of these transcription factors in maintaining homeostasis,we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling.The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation.Both gain-and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling.Moreover,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,respectively.In summary,this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle.With 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 

分 类 号：R542.2[医药卫生—心血管疾病]