Cigarette smoking is a leading cause of death and disease and, according to the CDC, is associated with over 430,000 premature deaths each year in the United States. Today, it is accepted that cigarette smoking increases the risk for myocardial infarction and stroke. While smoking does have many long term detrimental effects on the cardiovascular system the focus of this research is on the less studied effects that occur minutes to hours after cigarette exposure. Evidence suggests cigarette smoking increases platelet activation within minutes of exposure. Cigarette smoke exposes the user to a number of bioactive chemicals, one of the most well studied being nicotine. While nicotine itself does not have any significant effect on platelet activation it does result in increased plasma concentrations of numerous molecules including: catecholamines (epinephrine, norepinephrine, dopamine), and serotonin (5-HT). Elevation in the concentrations of each of these molecules in blood plasma has been associated with platelet activation leading to platelet aggregation and thrombus formation. However, the mechanisms by which cigarette smoking activates the platelets via these molecules is not known in detail, this project was designed to elucidate these mechanisms.
In exploring platelet physiology in cigarette smoking-associated elevated catecholamine and 5-HT plasma levels we performed initial ex vivo studies. Aggregation experiments demonstrated that the physiologic increases in these three weak prothrombotic molecules seen after smoking were not enough to directly cause aggregation individually but place platelets in a state of hypercoagulability where a secondary insult, such as collagen exposure, results in increased rates of aggregation and thrombus formation. Therefore, we hypothesize that they may have additive effect on platelet function using a novel mechanism at the intracellular level. This hypothesis is based on our further findings in the platelets of cigarette smokers that intracellular calcium and transglutaminase activity were elevated. Our findings with biochemical studies supported our hypothesis on smoking-associated catecholamine/5-HT signaling accelerates the internal trafficking dynamics of platelets. These changes result in platelet surface remodeling and upregulation of numerous proteins and glycans on the platelet membrane. Some of these surface molecules known to be involved with platelet aggregation while the others are newly discovered. These findings provide new insight into the pathophysiologic mechanisms involved in the hypercoagulability of cigarette smokers’ platelets and identify several novel targets for antithrombotic medications.
|Commitee:||Manolagas, Stavros C., Marsh, James D., Mcgehee, Robert E., Straub, Karl D.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Subjects:||Biology, Biochemistry, Physiology|
|Keywords:||Activation, Aggregation, Cigarettes, Platelets, Smoking, Thrombus|
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