Abstract 388: Small GTPase Rnd3 Fine-tunes Inflammatory Response in Myocardial Infarction

Abstract

Introduction: Myocardial infarction (MI) is a severe clinical condition caused by coronary artery thrombotic occlusion. According to the 2017 update from the American Heart Association, about 790,000 Americans have MI each year and 114,000 of those will die. Acute inflammation is developed post MI to clear necrotic myocardium and to guide the upcoming healing processes. A well-balanced and tightly-controlled inflammation, therefore, is critical for the post-MI cardiac recovery. We have previously demonstrated the essential roles of small GTPase Rnd3 in cardiac remodeling, calcium handling and angiogenesis. In the present study, we aimed to investigate Rnd3’s regulation of post-MI inflammation. Methods and results: Cardiac-specific Rnd3-deficient mice were subjected to MI operation and the hearts were dissected 3 days post MI. Rnd3-deficient hearts showed significantly enlarged infarct size and excessive inflammation than wild-type hearts. Importantly, we found that MI patients with lower Rnd3 expression levels exhibit a worse prognosis in cardiac function recovery. In the mechanistic study, hyperactivation of NF-kB signaling was observed in Rnd3-deficient cardiomyocytes and hearts post MI. Rnd3 blocks NF-kB nuclear translocation by disrupting the heterodimerization between p65 and p50. Finally, we generated transgenic mice with cardiac-specific overexpression of Rnd3. The mouse exhibited significantly preserved cardiac function and restrained inflammation post MI. Conclusions: This study identified Rnd3 as a fine-tuning factor mediating post-MI inflammation. Cardiac Rnd3 expression level positively correlates with MI patient prognosis. Thus, Rnd3 may serve as a potential therapeutic target for MI.