Abstract P2049: Myofibroblast Depletion Of Yap And Wwtr1 Improves Cardiac Function After Myocardial Infarction Via Ccn3 Suppression
| Autor: | Michael A Flinn, Santiago Alvarez, Makenna C Knas, Victor Alencar, Samantha Paddock, Xiaoxu Zhou, Tyler Buddell, Ayana Jamal, Pengyuan Liu, Jenny Drnevich, Michaela Patterson, Brian Link, Caitlin Omeara |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | The Hippo-Yap pathway is an area of interest in cardiac fibroblasts, as inhibition Lats1/2 promotes substantial fibrosis and Yap/Wwtr1 facilitate maturation of fibroblasts to myofibroblasts. While the Hippo-Yap pathway has been characterized in resting and activated fibroblasts, we take the novel approach of investigating its role in myofibroblasts. We assess depletion of Yap alone ( Yap fl/fl ;Postn MCM ) or Yap and Wwtr1 ( Yap fl/fl ;Wwtr1 fl/+ ;Postn MCM ) in myofibroblasts immediately following myocardial infarction and focus on identifying and validating downstream factors mediating pathological remodeling in mice. Following injury, depletion of Yap alone had no effect on heart function, but depletion of Yap and Wwtr1 resulted in improved ejection fraction and fractional shortening at 60 days post injury. Yap fl/fl , Wwtr1 fl/+ ;Postn MCM hearts also displayed smaller scars, reduced interstitial fibrosis, and more denatured collagen. Single cell RNA sequencing of interstitial cells 7 days post injury showed suppression of pro-fibrotic and pro-inflammatory genes and suppression of a matrifibrocyte phenotype in fibroblasts derived from the Yap fl/fl , Wwtr1 fl/+ ;Postn MCM heart. Analysis of in vivo and in vitro transcriptomics revealed depletion of Yap/Wwtr1 resulted in dramatically decreased fibroblast expression of the matricellular protein Ccn3. Administration of recombinant CCN3 to mice following injury aggravated cardiac function and scarring over the course of 28 days. Thus, we show Yap/Wwtr1 depletion in myofibroblasts attenuates fibrosis and significantly improves cardiac outcomes after injury and identify Ccn3 as a novel factor that contributes to adverse cardiac function. Given therapeutic strategies would likely be implemented after myocardial infarction when myofibroblasts are already activated, our work suggests targeting Yap and Wwtr1, or Ccn3 directly as an approach for suppressing pathological remodeling. |
| Databáze: | OpenAIRE |
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