Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes. Front Cardiovasc Med 2023;10:1142612
Date
04/01/2023Pubmed ID
36998974Pubmed Central ID
PMC10043314DOI
10.3389/fcvm.2023.1142612Scopus ID
2-s2.0-85150879131 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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 (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.
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 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.
DISCUSSION: 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.
Author List
Flinn MA, Alvarez-Argote S, Knas MC, Almeida VA, Paddock SJ, Zhou X, Buddell T, Jamal A, Taylor R, Liu P, Drnevich J, Patterson M, Link BA, O'Meara CCAuthors
Michael Andrew Flinn Postdoctoral Fellow in the Physiology department at Medical College of WisconsinBrian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
