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dc.contributor.advisorMcDonagh, Paul F.en_US
dc.contributor.authorHokama, Jason Yoshitsune
dc.creatorHokama, Jason Yoshitsuneen_US
dc.date.accessioned2013-04-25T09:53:39Zen
dc.date.available2013-04-25T09:53:39Zen
dc.date.issued1999en_US
dc.identifier.urihttp://hdl.handle.net/10150/284055en
dc.description.abstractDiabetes is now considered a major risk factor for cardiovascular disease, particularly ischemic heart disease. Although restoration of coronary blood flow is prudent in order to salvage the region of the myocardium at risk, reperfusion is also associated with an additional injury to the heart. This is known as myocardial ischemia-reperfusion (I-R) injury. The diabetic heart appears to be more susceptible to I-R injury compared to non-diabetic hearts when blood is used as the perfusate suggesting that components within diabetic blood may play a role in exacerbating the damage to the diabetic heart upon reperfusion. In a series of experiments, we tested the hypothesis that leukocytes are retained in the coronary microcirculation to a significant extent early in reperfusion following ischemia. We also examined if diabetic PMNs are hyperactivated, and are able to respond to exogenous inflammatory stimuli. Since diabetic blood is known to be hypercoagulable, we tested the hypothesis that platelet activation adhesion protein expression is increased in diabetic blood. Finally, we examined if platelet-PMN interactions are increased in diabetic blood. Our results indicate that, early in reperfusion following ischemia, leukocyte retention in the coronary capillaries and post-capillary venules is significantly increased in diabetic hearts compared to non-diabetic hearts. Our findings also indicate that PMNs from diabetics are hyperactivated compared to nondiabetic PMNs suggesting that, once sequestered, PMNs in the diabetic coronary microcirculation are able to initiate an exaggerated inflammatory response, which may exacerbate the reperfusion injury. We also found that platelet adhesion protein expression was enhanced in diabetics, an effect that was partially attenuated by aspirin usage. Platelet-PMN conjugate formation was increased in diabetic blood and appeared to enhance ROS production in diabetic PMNs since blockade of these aggregates attenuated PMN ROS production in diabetic blood. The results from these experiments indicate that both hyperactivated PMNs and platelets in diabetic blood likely contribute to exacerbated ischemia-reperfusion injury in the diabetic heart. Once the mechanisms of myocardial reperfusion injury in diabetes are known, therapeutic interventions can be introduced with the hope of attenuating the increased morbidity and mortality associated with ischemic heart disease in the diabetic population.
dc.language.isoen_USen_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.subjectBiology, Animal Physiology.en_US
dc.subjectHealth Sciences, Medicine and Surgery.en_US
dc.subjectHealth Sciences, Immunology.en_US
dc.titleBlood cell alterations in diabetes: Implications for ischemia-reperfusion injury in the diabetic hearten_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.identifier.proquest9960256en_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.namePh.D.en_US
dc.identifier.bibrecord.b4027441xen_US
refterms.dateFOA2018-06-27T04:37:32Z
html.description.abstractDiabetes is now considered a major risk factor for cardiovascular disease, particularly ischemic heart disease. Although restoration of coronary blood flow is prudent in order to salvage the region of the myocardium at risk, reperfusion is also associated with an additional injury to the heart. This is known as myocardial ischemia-reperfusion (I-R) injury. The diabetic heart appears to be more susceptible to I-R injury compared to non-diabetic hearts when blood is used as the perfusate suggesting that components within diabetic blood may play a role in exacerbating the damage to the diabetic heart upon reperfusion. In a series of experiments, we tested the hypothesis that leukocytes are retained in the coronary microcirculation to a significant extent early in reperfusion following ischemia. We also examined if diabetic PMNs are hyperactivated, and are able to respond to exogenous inflammatory stimuli. Since diabetic blood is known to be hypercoagulable, we tested the hypothesis that platelet activation adhesion protein expression is increased in diabetic blood. Finally, we examined if platelet-PMN interactions are increased in diabetic blood. Our results indicate that, early in reperfusion following ischemia, leukocyte retention in the coronary capillaries and post-capillary venules is significantly increased in diabetic hearts compared to non-diabetic hearts. Our findings also indicate that PMNs from diabetics are hyperactivated compared to nondiabetic PMNs suggesting that, once sequestered, PMNs in the diabetic coronary microcirculation are able to initiate an exaggerated inflammatory response, which may exacerbate the reperfusion injury. We also found that platelet adhesion protein expression was enhanced in diabetics, an effect that was partially attenuated by aspirin usage. Platelet-PMN conjugate formation was increased in diabetic blood and appeared to enhance ROS production in diabetic PMNs since blockade of these aggregates attenuated PMN ROS production in diabetic blood. The results from these experiments indicate that both hyperactivated PMNs and platelets in diabetic blood likely contribute to exacerbated ischemia-reperfusion injury in the diabetic heart. Once the mechanisms of myocardial reperfusion injury in diabetes are known, therapeutic interventions can be introduced with the hope of attenuating the increased morbidity and mortality associated with ischemic heart disease in the diabetic population.


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