Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.
Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.
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DOI：
10.1093/eurheartj/ehac818
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发表时间：
2023-03-07
影响因子：
39.3
通讯作者：
Aikawa, Elena
中科院分区：
文献类型：
--
作者：
Iqbal, Farwah;Schlotter, Florian;Becker-Greene, Dakota;Lupieri, Adrien;Goettsch, Claudia;Hutcheson, Joshua D.;Rogers, Maximillian A.;Itoh, Shinsuke;Halu, Arda;Lee, Lang Ho;Blaser, Mark C.;Mlynarchik, Andrew K.;Hagita, Sumihiko;Kuraoka, Shiori;Chen, Hao Yu;Engert, James C.;Passos, Livia S. A.;Jha, Prabhash K.;Osborn, Eric A.;Jaffer, Farouc A.;Body, Simon C.;Robson, Simon C.;Thanassoulis, George;Aikawa, Masanori;Singh, Sasha A.;Sonawane, Abhijeet R.;Aikawa, Elena
钙化性主动脉瓣疾病（CAVD）是最常见的瓣膜疾病，由炎症、纤维化和钙化的慢性相互作用组成。在本研究中，SORT1被确定为CAVD病理生理中的一个新的关键角色，并探讨了其在瓣膜间质细胞（VICs）向病理表型转化中的作用。采用sortilin缺乏的主动脉瓣（AV）丝损伤（AVWI）小鼠模型，研究sortilin对AV狭窄、纤维化和钙化的影响。体外实验采用在成骨条件下培养7、14和21天的人原代vic；并进行成像、蛋白质组学和转录组学处理，包括单细胞rna测序（scRNA-seq）。AVWI小鼠模型显示，与对照组相比，sortilin缺陷小鼠的AV纤维化、钙化和狭窄程度降低。蛋白质研究确定了人类vic向由sortilin介导的肌成纤维细胞样表型的转变。Sortilin功能丧失减少体外VIC钙化。ScRNA-seq鉴定了人类VIC样本中12个差异表达的细胞簇，其中检测到一种新的炎症性肌成纤维-成骨性VIC （IMO-VIC）表型，SORT1、COL1A1、WNT5A、IL-6和血清淀粉样蛋白A1的表达增加。sortilin缺乏的vic序列显示IMO-VIC表型降低。Sortilin通过介导瓣膜纤维化和钙化促进CAVD，这是一种新发现的表型（IMO-VIC）。这是第一个研究sortilin在瓣膜钙化中的作用的研究，它可能使其成为抑制IMO-VIC出现的治疗靶点，同时减少炎症、纤维化和钙化，这是CAVD的三个关键病理过程。多组学方法鉴定sortilin在钙化性主动脉瓣疾病（CAVD）中介导纤维化和钙化中的作用。Sort1野生型（Sort1+/+）和Sort1缺失型（Sort1−/−）小鼠主动脉瓣（AV）丝损伤后，AVs胶原沉积和钙化减少。从人CAVD组织中收集瓣膜间质细胞（VICs）并在成骨条件下培养。在培养的不同时间点（第7、14和21天）收集的VICs进行流式细胞术、蛋白质组学和单细胞rna测序（scRNA-seq）处理。多组学数据表明，在vic成骨培养后，sortilin表达增加。蛋白分析和scRNA-seq检测发现sortilin表达调控WNT5a、MAPK、YAP和IL-6的表达增加。ScRNA-seq鉴定了一个过渡性VIC亚群，其具有活化的肌成纤维细胞表型，后来转变为肌成纤维细胞和成骨细胞的组合表型。ScRNA-seq数据鉴定了炎症性肌成纤维-成骨性VIC （IMO-VIC）亚群，该亚群可能是sortilin调节下CAVD发病机制的关键参与者。
Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD. Multi-omic approach to identify the role of sortilin in mediating fibrosis and calcification in calcific aortic valve disease (CAVD). Aortic valve (AV) wire injury in sortilin wild-type (Sort1+/+) and deficient mice (Sort1−/−) showed decreased collagen deposition and calcification in mouse AVs. Valvular interstitial cells (VICs) were collected from human CAVD tissue and cultured in osteogenic conditions. VICs collected at varying time points of culture (Days 7, 14, and 21) were processed for flow cytometry, proteomics, and single-cell RNA-sequencing (scRNA-seq). Multiomics data identified increased sortilin expression following the osteogenic culture of VICs. Protein analysis and scRNA-seq identified increased expression of WNT5a, MAPK, YAP, and IL-6 regulated by the expression of sortilin. ScRNA-seq identified a transitionary VIC subpopulation with an activated myofibroblast phenotype that later transitioned into a combined myofibroblast and osteogenic phenotype. ScRNA-seq data identified an inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) subpopulation that may be a key player in the pathogenesis of CAVD under the regulation of sortilin.
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影响因子：
29
作者：
Kjolby, Mads;Andersen, Olav M.;Nykjaer, Anders
通讯作者：
Nykjaer, Anders
全基因组关联研究，用于冠状动脉钙化，随访心肌梗塞。
影响因子：
37.8
作者：
O'Donnell CJ;Kavousi M;Smith AV;Kardia SL;Feitosa MF;Hwang SJ;Sun YV;Province MA;Aspelund T;Dehghan A;Hoffmann U;Bielak LF;Zhang Q;Eiriksdottir G;van Duijn CM;Fox CS;de Andrade M;Kraja AT;Sigurdsson S;Elias-Smale SE;Murabito JM;Launer LJ;van der Lugt A;Kathiresan S;CARDIoGRAM Consortium;Krestin GP;Herrington DM;Howard TD;Liu Y;Post W;Mitchell BD;O'Connell JR;Shen H;Shuldiner AR;Altshuler D;Elosua R;Salomaa V;Schwartz SM;Siscovick DS;Voight BF;Bis JC;Glazer NL;Psaty BM;Boerwinkle E;Heiss G;Blankenberg S;Zeller T;Wild PS;Schnabel RB;Schillert A;Ziegler A;Münzel TF;White CC;Rotter JI;Nalls M;Oudkerk M;Johnson AD;Newman AB;Uitterlinden AG;Massaro JM;Cunningham J;Harris TB;Hofman A;Peyser PA;Borecki IB;Cupples LA;Gudnason V;Witteman JC
通讯作者：
Witteman JC
影响因子：
48
作者：
Korsunsky, Ilya;Millard, Nghia;Raychaudhuri, Soumya
通讯作者：
Raychaudhuri, Soumya
影响因子：
37.8
作者：
Aikawa E;Aikawa M;Libby P;Figueiredo JL;Rusanescu G;Iwamoto Y;Fukuda D;Kohler RH;Shi GP;Jaffer FA;Weissleder R
通讯作者：
Weissleder R
DOI：
10.15420/ecr.2015.10.2.108
发表时间：
2015
期刊：
European cardiology
影响因子：
--
作者：
Lerman DA;Prasad S;Alotti N
通讯作者：
Alotti N