PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Mahipal Singh, Chuanfu Li, Yue Zou, Tom Ecay, Antonio Rusinol
Sympathetic stimulation occurs in the heart after injuries such as ischemia/reperfusion (I/R) and myocardial infarction and affects myocardial remodeling. Prolonged sympathetic stimulation can result in myocardial dysfunction through its effects on cardiac myocyte apoptosis and myocardial fibrosis. Ubiquitin (UB) is well known for its role of tagging old or damaged proteins for degradation via the UB-proteosome pathway. The role of exogenous UB however, is not fully understood. Previously, our lab showed that β-adrenergic receptor (β-AR) stimulation increased levels of extracellular UB in the conditioned media of adult rat ventricular myocytes and that UB inhibits β-AR-stimulated apoptosis. This study investigates the role of extracellular UB after myocardial I/R injury in terms of infarct size, function, inflammation and proteomic changes in vivo as well as the effects of extracellular UB on cardiac fibroblast function in vitro. First, we validated a method of consistently measuring real-time myocardial ischemia and reperfusion in vivo. Second, cardiac function was studied 3 days post I/R injury in the presence or absence of UB infusion. Echocardiographic analysis determined UB infusion increased cardiac function after I/R injury in terms of ejection fraction and fractional shortening. UB decreased infarct size and infiltration of inflammatory cells including neutrophils and macrophages as well as reduced activity of neutrophils. UB increased protein levels of matrix metalloproteinase (MMP)-2 and transforming growth factor-β1 and increased activity of MMP-9. Third, in adult rat primary cardiac fibroblasts, we demonstrate that extracellular UB interacts with CXCR-4. UB treatment decreased serum-mediated increases in fibroblast proliferation and enhanced the contraction of fibroblast-populated collagen gels. Thus, extracellular UB likely interacts with CXCR-4 to influence fibroblast function and proliferation. Additionally, UB influences cardiac remodeling in terms of heart function, infarct size, inflammatory response and proteomic profile.
Dissertation - Open Access
Scofield, Stephanie, "Exogenous Ubiquitin: Role in Myocardial Inflammation and Remodeling Post- Ischemia/Reperfusion Injury" (2017). Electronic Theses and Dissertations. Paper 3347. https://dc.etsu.edu/etd/3347
Copyright by the authors.