PDF(Pubmed)
Abstract：
UNASSIGNED: While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored.
UNASSIGNED: We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone (Yap fl/fl ;Postn MCM ) or Yap and Wwtr1 (Yap fl/fl ;Wwtr1 fl/+ ;Postn MCM ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling.
UNASSIGNED: Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening. Single cell RNA sequencing of interstitial cardiac cells 7 days post infarction showed suppression of pro-fibrotic genes in fibroblasts derived from Yap fl/fl ,Wwtr1 fl/+ ;Postn MCM hearts. In vivo myofibroblast depletion of Yap/Wwtr1 as well in vitro knockdown of Yap/Wwtr1 dramatically decreased RNA and protein expression of the matricellular factor Ccn3. Administration of recombinant CCN3 to adult mice following myocardial infarction remarkably aggravated cardiac function and scarring. CCN3 administration drove myocardial gene expression of pro-fibrotic genes in infarcted left ventricles implicating CCN3 as a novel driver of cardiac fibrotic processes following myocardial infarction.
UNASSIGNED: Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after myocardial infarction and we identify Ccn3 as a factor downstream of Yap/Wwtr1 that contributes to adverse cardiac remodeling post MI. Myofibroblast expression of Yap, Wwtr1, and Ccn3 could be further explored as potential therapeutic targets for modulating adverse cardiac remodeling post injury.
UNASSIGNED: We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone (Yap fl/fl ;Postn MCM ) or Yap and Wwtr1 (Yap fl/fl ;Wwtr1 fl/+ ;Postn MCM ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling.
UNASSIGNED: Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening. Single cell RNA sequencing of interstitial cardiac cells 7 days post infarction showed suppression of pro-fibrotic genes in fibroblasts derived from Yap fl/fl ,Wwtr1 fl/+ ;Postn MCM hearts. In vivo myofibroblast depletion of Yap/Wwtr1 as well in vitro knockdown of Yap/Wwtr1 dramatically decreased RNA and protein expression of the matricellular factor Ccn3. Administration of recombinant CCN3 to adult mice following myocardial infarction remarkably aggravated cardiac function and scarring. CCN3 administration drove myocardial gene expression of pro-fibrotic genes in infarcted left ventricles implicating CCN3 as a novel driver of cardiac fibrotic processes following myocardial infarction.
UNASSIGNED: Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after myocardial infarction and we identify Ccn3 as a factor downstream of Yap/Wwtr1 that contributes to adverse cardiac remodeling post MI. Myofibroblast expression of Yap, Wwtr1, and Ccn3 could be further explored as potential therapeutic targets for modulating adverse cardiac remodeling post injury.
摘要：
■虽然Yap和Wwtr1调节心脏损伤后常驻心脏成纤维细胞向肌成纤维细胞分化，它们在激活的肌成纤维细胞中的具体作用仍有待探索。
■我们评估了在心肌梗死后成年小鼠肌成纤维细胞中单独使用Yap（Yapfl/fl；PostnMCM）或Yap和Wwtr1（Yapfl/fl；Wwtr1fl/；PostnMCM）的遗传耗竭的病理生理和细胞后果，并鉴定和验证了特定于心脏肌成纤维细胞介导病理性重塑的新型下游
■心肌梗死后，肌成纤维细胞中Yap的消耗对心脏功能的影响最小，而Yap/Wwtr1的消耗导致较小的疤痕，减少间质纤维化，改善射血分数和缩短分数。梗死后7天，间质心肌细胞的单细胞RNA测序显示，源自Yapfl/fl的成纤维细胞中的促纤维化基因受到抑制，Wwtr1fl/+；张贴MCM心脏。Yap/Wwtr1的体内成肌纤维细胞耗竭以及Yap/Wwtr1的体外敲除大大降低了基质细胞因子Ccn3的RNA和蛋白质表达。在心肌梗死后对成年小鼠施用重组CCN3显著加重心脏功能和瘢痕形成。CCN3给药驱动梗死左心室中促纤维化基因的心肌基因表达，暗示CCN3是心肌梗死后心脏纤维化过程的新驱动因素。
■肌成纤维细胞中的Yap/Wwtr1耗竭可减弱纤维化并显著改善心肌梗死后的心脏预后，我们发现Ccn3是Yap/Wwtr1下游的一个因子，可导致MI后的不良心脏重塑。Yap的成肌纤维细胞表达,Wwtr1和Ccn3可以进一步探索作为调节损伤后不良心脏重塑的潜在治疗靶标。
■我们评估了在心肌梗死后成年小鼠肌成纤维细胞中单独使用Yap（Yapfl/fl；PostnMCM）或Yap和Wwtr1（Yapfl/fl；Wwtr1fl/；PostnMCM）的遗传耗竭的病理生理和细胞后果，并鉴定和验证了特定于心脏肌成纤维细胞介导病理性重塑的新型下游
■心肌梗死后，肌成纤维细胞中Yap的消耗对心脏功能的影响最小，而Yap/Wwtr1的消耗导致较小的疤痕，减少间质纤维化，改善射血分数和缩短分数。梗死后7天，间质心肌细胞的单细胞RNA测序显示，源自Yapfl/fl的成纤维细胞中的促纤维化基因受到抑制，Wwtr1fl/+；张贴MCM心脏。Yap/Wwtr1的体内成肌纤维细胞耗竭以及Yap/Wwtr1的体外敲除大大降低了基质细胞因子Ccn3的RNA和蛋白质表达。在心肌梗死后对成年小鼠施用重组CCN3显著加重心脏功能和瘢痕形成。CCN3给药驱动梗死左心室中促纤维化基因的心肌基因表达，暗示CCN3是心肌梗死后心脏纤维化过程的新驱动因素。
■肌成纤维细胞中的Yap/Wwtr1耗竭可减弱纤维化并显著改善心肌梗死后的心脏预后，我们发现Ccn3是Yap/Wwtr1下游的一个因子，可导致MI后的不良心脏重塑。Yap的成肌纤维细胞表达,Wwtr1和Ccn3可以进一步探索作为调节损伤后不良心脏重塑的潜在治疗靶标。
