Doctoral Dissertations

Date of Award

8-2003

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Xuemin Xu

Abstract

LPA is a component of oxidized low density lipoproteins (oxLDL) which has been shown to accumulate in human atherosclerotic plaques. Tissue factor {TF) is the principal initiator of blood coagulation. Tissue factor upregulation in atherosclerotic plaque can lead to undesirable vascular thrombosis. The generation of reactive oxygen species (ROS), which act as signaling molecules in the vascular system, is enhanced in response to injury and has been associated with a procoagulant state and the progression of atherosclerotic disease. Oxidative stress might contribute to the increased expression of proatherosclerotic genes at sites of vascular injury, including TF. Little is known about the regulation of TF by LPA in smooth muscle cells (SMC) which is a major player in the process of atherosclerosis. Data generated by this study demonstrate that LP A markedly induces TF expression in rat aorta smooth muscle cells (RASMCs) and human aorta smooth muscle cells (HASMCs). The signaling pathways involved are multiple. One signaling pathway demonstrates that LP A activates Gai protein which in tum activates PKC and MAPK cascades to induce Egr-1 that is involved in turning on TF gene in the nucleus. The other pathways include LP A-induced release of ROS and calcium, mediated by PLA2 or without PLA2 involvement. Our data suggest that elevated LP A have potential atherogenic and thrombogenic actions by inducing TF expression and ROS release. Understanding the mechanisms involved could provide new insights into atherosclerosis, thrombosis and restenosis after angioplasty.

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