Doctor of Philosophy
Lowe-Krentz, Linda J.
Other advisers/committee members
Kuchka, Michael; Iovine, M. Katherine; Berger, Bryan
Atherosclerosis, an inflammatory disease characterized by the hardening of the arteries and often attributed to poor life style choices, is the leading cause of death in the United States, Europe, and most of Asia. This disease is caused by injury to the arterial wall, causing an inflammatory response which can become misregulated, and over the lifetime of an individual can lead to plaque formation. Hallmarks of atherosclerotic plaque formation include the proliferation and migration of vascular smooth muscle cells (VSMCs) to the injured site in the arterial wall and endothelial cell dysfunction, both of which contribute to plaque formation. In an attempt to control this unwarranted inflammation and cellular proliferation, heparin has been studied because of its anti-inflammatory and anti-proliferative effects. Unfortunately, the mechanisms by which heparin induces these effects are not well understood. In this study, experiments aimed at identification of a receptor for heparin furthered the understanding of the signaling mechanisms underlying heparin's anti-inflammatory and anti-proliferative effects. To gain a better understanding of the underlying signaling cascade induced by heparin, various gene expression analyses were performed in heparin-treated VSMCs. While heparin is one of the major signals opposing vascular disease progression, other signals including laminar shear stress also provide similar opposing actions. Along with investigation of heparin signaling, experiments demonstrating a role for cofilin in actin remodeling during laminar shear stress have been completed. Cofilin, a member of the Actin Depolymerizing Factor family of proteins, is an actin severing protein which promotes actin depolymerization from the actin minus end when cofilin is unphosphorylated. This work also underscored the importance of cofilin and actin realignment in shear stress-induced endothelial barrier integrity. The culmination of this work has unveiled a deeper understanding of the molecular mechanisms underlying atherosclerosis and the anti-inflammatory effects of heparin and laminar shear stress.
Slee, Joshua B., "Elucidating the Anti-Inflammatory Roles of Heparin and Shear Stress in Atherosclerosis" (2014). Theses and Dissertations. 1629.