文献检索，用中文搜 PubMed

INTRODUCTION

While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored.

METHODS

We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone ( ; ) or Yap and Wwtr1 ( ; ; ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling.

RESULTS

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 , ; 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.

DISCUSSION

Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after myocardial infarction and we identify 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.

INTRODUCTION

While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored.

METHODS

RESULTS

DISCUSSION

引言

虽然Yap和Wwtr1在心脏损伤后调节心脏成纤维细胞向肌成纤维细胞分化，但它们在活化肌成纤维细胞中的具体作用仍未得到探索。

方法

我们评估了成年小鼠心肌梗死后单独基因敲除Yap（；）或同时敲除Yap和Wwtr1（；；）在肌成纤维细胞中的病理生理和细胞后果，并鉴定和验证了心肌成纤维细胞中特异性介导病理重塑的新下游因子。

结果

心肌梗死后，肌成纤维细胞中Yap的缺失对心脏功能影响极小，而Yap/Wwtr1的缺失导致瘢痕更小、间质纤维化减少、射血分数和缩短分数改善。梗死后7天对间质心脏细胞进行单细胞RNA测序显示，源自，；心脏的成纤维细胞中促纤维化基因受到抑制。体内肌成纤维细胞中Yap/Wwtr1的缺失以及体外Yap/Wwtr1的敲低显著降低了基质细胞因子Ccn3的RNA和蛋白表达。心肌梗死后给成年小鼠注射重组CCN3显著加重了心脏功能和瘢痕形成。注射CCN3驱动梗死左心室中促纤维化基因的心肌基因表达，表明CCN3是心肌梗死后心脏纤维化过程的新驱动因素。