Persistent Link:
http://hdl.handle.net/10150/289926
Title:
Mechanisms of platelet activation in type 2 diabetes
Author:
Cohen, Zoe
Issue Date:
2003
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Diabetics suffer from a pro-thrombotic condition. It is established that platelets are activated in type 2 diabetes. However the mechanisms of platelet activation in this disease are not yet known. The purpose of these studies was to elucidate the mechanisms of platelet activation and the effect these mechanisms have on type 2 diabetic platelets. Apoptosis of cells is regulated by caspases, a group of cysteine proteases. When platelets become activated, they express phosphatidylserine (PS) on the outer leaflet of the plasma membrane as well as form platelet microparticles (PMPs). In addition, platelets aggregate when activated. We found that platelets from diabetic subjects contain activated caspases. These platelets also formed increased numbers of PMPs compared to platelets from non-diabetic subjects. We observed a 30-fold increase in thrombin activity in the plasma from diabetics. To determine if caspases were involved in platelet activation, we determined if caspase inhibition (using the pan-caspase inhibitor zVAD-fmk); (1) decreased PS expression and (2) decreased platelet aggregation following activation. We found that platelets treated with zVAD-fmk significantly decreased A23187-induced PS exposure as well as aggregation. There is limited information on the role of caspases on platelet adhesion proteins such as P-selectin or GPIIb/IIIa during platelet activation. Therefore, we tested if caspase inhibition attenuated P-selectin and GPIIb/IIIa expression. Using blood from non-diabetic volunteers, we found that treatment with zVAD-fmk caused a significant attenuation of P-selectin expression in stimulated platelets. Together these data suggest that caspases play a novel role in platelet activation. We also wanted to determine if treating type 2 diabetic rats (Zucker Diabetic Fatty rats, ZDF) with the caspase inhibitor zVAD-fmk in vivo ; (1) attenuated PS expression, (2) attenuated platelet microparticle (PMP) formation and (3) attenuated platelet aggregation. ZDF rats were treated in vivo with 40 μg zVAD-fmk for 4 days. We found attenuated PS exposure, PMP formation as well as decreased aggregation in ZDF rats treated with zVAD-fmk. Our overall results demonstrate a novel role of caspases in platelet activation. Together, these studies may lead to development of novel treatments for pathophysiologic states associated with platelet activation such as diabetes, myocardial infarction, and stroke.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Animal Physiology.; Health Sciences, Immunology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Physiological Sciences
Degree Grantor:
University of Arizona
Advisor:
McDonagh, Paul F.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleMechanisms of platelet activation in type 2 diabetesen_US
dc.creatorCohen, Zoeen_US
dc.contributor.authorCohen, Zoeen_US
dc.date.issued2003en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractDiabetics suffer from a pro-thrombotic condition. It is established that platelets are activated in type 2 diabetes. However the mechanisms of platelet activation in this disease are not yet known. The purpose of these studies was to elucidate the mechanisms of platelet activation and the effect these mechanisms have on type 2 diabetic platelets. Apoptosis of cells is regulated by caspases, a group of cysteine proteases. When platelets become activated, they express phosphatidylserine (PS) on the outer leaflet of the plasma membrane as well as form platelet microparticles (PMPs). In addition, platelets aggregate when activated. We found that platelets from diabetic subjects contain activated caspases. These platelets also formed increased numbers of PMPs compared to platelets from non-diabetic subjects. We observed a 30-fold increase in thrombin activity in the plasma from diabetics. To determine if caspases were involved in platelet activation, we determined if caspase inhibition (using the pan-caspase inhibitor zVAD-fmk); (1) decreased PS expression and (2) decreased platelet aggregation following activation. We found that platelets treated with zVAD-fmk significantly decreased A23187-induced PS exposure as well as aggregation. There is limited information on the role of caspases on platelet adhesion proteins such as P-selectin or GPIIb/IIIa during platelet activation. Therefore, we tested if caspase inhibition attenuated P-selectin and GPIIb/IIIa expression. Using blood from non-diabetic volunteers, we found that treatment with zVAD-fmk caused a significant attenuation of P-selectin expression in stimulated platelets. Together these data suggest that caspases play a novel role in platelet activation. We also wanted to determine if treating type 2 diabetic rats (Zucker Diabetic Fatty rats, ZDF) with the caspase inhibitor zVAD-fmk in vivo ; (1) attenuated PS expression, (2) attenuated platelet microparticle (PMP) formation and (3) attenuated platelet aggregation. ZDF rats were treated in vivo with 40 μg zVAD-fmk for 4 days. We found attenuated PS exposure, PMP formation as well as decreased aggregation in ZDF rats treated with zVAD-fmk. Our overall results demonstrate a novel role of caspases in platelet activation. Together, these studies may lead to development of novel treatments for pathophysiologic states associated with platelet activation such as diabetes, myocardial infarction, and stroke.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Animal Physiology.en_US
dc.subjectHealth Sciences, Immunology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMcDonagh, Paul F.en_US
dc.identifier.proquest3106977en_US
dc.identifier.bibrecord.b44649241en_US
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