Degree

Doctor of Philosophy (PhD)

Department

School of Animal Sciences

Document Type

Dissertation

Abstract

Cardiac myofibroblasts (CMFs) are specialized cardiac fibroblasts (CFs) expressing abundant actin stress fiber. However, the role of CMF contraction in post-myocardial infarction (MI) cardiac repair have not been defined yet. Here, we generated cardiac fibroblast–specific deletion of Myh9 to uncovers the pivotal role of non‑muscle myosin IIA in regulating fibroblast behavior in cultured condition and during myocardial repair. We found that Myh9 knockout (KO) significantly affected CMF morphology, completely abolished the stress fiber formation and contraction, and reduced their proliferation and motility. Mice lacking Myh9 in CFs have an increased post-MI cardiac rupture rate and reduced stress fiber formation, collagen deposition, fibrosis and systolic function. Transcriptomic, epigenetic, and proteomics analyses revealed disrupted expression of stress fiber and mesenchymal identity genes/proteins caused by Myh9 KO. Pharmacologic manipulation of RhoA and yes-associated protein (YAP) activity partially restored the differentiation of CMFs caused by Myh9 loss in vitro, highlighting a compensatory axis. Mechanistically, Myh9 KO led to an increased globular to filamentous actin (G/F-actin) ratio, decreased MRTFA activity, and altered epigenetic modification, which all contributed to trigger multiple consequences observed in cultured cells and mice lacking Myh9, demonstrating the indispensable role of Myh9 in maintaining normal CMF activity and promoting post-injury heart healing.

Date

7-11-2025

Committee Chair

Xing Fu

DOI

10.31390/gradschool_dissertations.6853

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Available for download on Monday, July 10, 2028

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