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Delineating mechanisms of endothelial cytoprotection by APC

Institution: University of California, San Diego
Investigator(s): Jim Kim Soh, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20FT-0074 Award: $65,805
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Tobacco use is the leading risk factor contributing to premature mortality in the United States. One in five deaths from cardiovascular disease is attributed to smoking and accounts for over $157 billion annually in health-related economic costs. The detrimental effects of tobacco use include increased risk of hypertension and heart attacks where interruption of blood supply and subsequent oxygen deprivation to the heart causes heart cells to die. The most common cause of a heart attack is a blocked coronary artery caused by dislodged atherosclerotic deposits or plaques, masses of fatty acids and white blood cells that accumulate in the endothelium, a thin layer of cells that line the inner surface of blood vessels and is in contact with circulating blood. The endothelium acts as a barrier between the blood circulatory system and the surrounding tissue allowing selective passage of materials and plays important roles in blood clotting and blood pressure regulation.

Cigarette smoke contains more than 60 known cancer-causing and toxic substances that promote endothelial cell injury and dysfunction by initiating inflammation and accumulation of atherosclerotic plaques in the endothelium. Smoking-induced endothelial dysfunction is an early event that contributes to the progression of chronic cardiovascular disease and has been linked to decreased levels of activated Protein C (APC), a naturally occurring anti-clotting agent in the blood. Human recombinant APC is the first FDA-approved drug for the treatment of severe sepsis, a life-threatening clinical condition resulting from uncontrolled inflammation and dysregulated blood clotting. The processes by which APC function remains poorly understood.

The proposed studies will examine the role of APC in reducing endothelial inflammation to maintain endothelial barrier function and will provide a comprehensive pharmacological study of APC’s anti-inflammatory effects in endothelial cells from different types of blood vessels. Understanding how APC functions to protect the endothelium from inflammation caused by tobacco use will enable development of new strategies for drug targets in the prevention and treatment of tobacco-related cardiovascular disease and is expected to have substantial impact in reducing healthcare costs related to tobacco use.

Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestin and dishevelled-2 scaffolds
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Unice J.K. Soh and JoAnn Trejo ART
Yr: 2011 Vol: 108 Nbr: 50 Abs: Pg: E1372-80