Novel Insights into the Mechanistic Role of Small Rho GTPase in Chronic Cardiac Fibrotic Remodeling - PROJECT DESCRIPTION/ABSTRACT The transactivation of cardiac fibroblasts plays a dual role in the process of repairing and remodeling the heart following myocardial infarction (MI). During the post-injury acute phase, cardiac fibroblast is activated and highly proliferative, which plays an essential role in preventing cardiac rupture and facilitating wound healing. However, prolonged and excessive cardiac fibrosis is detrimental to the heart. Striking a balance between the short-term benefits and avoiding long-term negative consequences associated with cardiac fibroblast transdifferentiation has posed a significant challenge in the research field. During the cardiac remodeling process, nature has evolved an adaptive mechanism to limit excessive fibrosis by promoting the apoptosis of myofibroblasts and reducing extracellular matrix (ECM) protein expression. Unfortunately, these innate signals are often insufficient to prevent chronic fibrosis, likely due to their delayed and passive activation. In this proposal, we hypothesize that early activation of adaptive anti-fibrotic signals may offer cardiac protection in post-MI remodeling. To achieve this overarching goal, we performed data mining in the publicly available scRNA-seq databases. We identified the downregulation of a small GTPase, RHOE, as a potential adaptive anti-fibrotic signal in heart failure patients. We propose to explore the dynamic role of fibroblast RHOE in post-MI cardiac remodeling. Comprehensive experimental approaches and multiple genetic animal models have been established and will be applied to investigate the functional role and mechanisms underlining RHOE-mediated chronic cardiac fibrosis. This project is a proof-of-concept study to selectively mitigate prolonged fibrosis without interrupting the acute wound repair after ischemia injury, shedding light on novel therapeutic strategies. We expect to achieve two main objectives: 1) defining the functional and pathological significance of RhoE in post-MI heart and 2) uncovering novel non-canonical mechanisms through which RhoE modulates ECM reconstitution.
