Effects of Age and Immune Dysfunction on the Cardiac Extracellular Matrix and Diastolic Function

Persistent Link:
http://hdl.handle.net/10150/195581
Title:
Effects of Age and Immune Dysfunction on the Cardiac Extracellular Matrix and Diastolic Function
Author:
Alwardt, Cory M.
Issue Date:
2005
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:
Cardiomyopathies are often initiated by diastolic dysfunction, and treatment of diastolic dysfunction remains empirical with an emphasis on prevention. This dissertation focuses on the mechanism of cardiomyopathy and diastolic dysfunction during aging and immune dysfunction. The governing hypothesis is that altered cytokine release such as that seen during aging and immune dysfunction can lead to diastolic dysfunction and myocardial fibrosis. Our first study examined the role of aging and immunosenescence on the cardiac extracellular matrix (ECM) and left ventricular stiffness. We demonstrated age-related immune dysfunction, myocardial fibrosis, and diastolic dysfunction. We also found that exogenous dehydroepiandrosterone (DHEA), an adrenal steroid hormone popular due to its anti-aging effects, partially reversed these pathologies in aged mice. In this model, fibrosis and its reversal were associated with altered regulation of matrix metalloproteinases (MMP) and collagen cross-linking. We propose two mechanisms for the protective effects of DHEA: (1) a direct effect on cardiac fibroblasts, or (2) downstream effects of immune modulation. In the subsequent study, we found that DHEA is capable of directly altering cardiac fibroblasts, suggesting a mechanism for the effects of DHEA on cardiac function. Due to pleiotropic effects of DHEA, we decided to specifically target the immune system using T-cell receptor peptides during murine AIDS(mAIDS). Mice with mAIDS suffer from cardiomyopathy in the absence of myocarditis and opportunistic pathogens. We demonstrated that reversal of immune dysfunction in mAIDS was associated with reversal of myocardial fibrosis and ventricular stiffness. In conclusion, we have demonstrated age- and immune-related diastolic dysfunction that can be reversed by modulation of the T-cells of the immune system. Immune modulation should be further investigated as a therapeutic target to treat diastolic dysfunction during immune dysfunction. We also found that MMPs and collagen cross-linking are highly involved in extracellular matrix regulation in the models used in this dissertation.
Type:
text; Electronic Dissertation
Keywords:
cardiomyopathy; MMP; mice; mAIDS; DHEA
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Larson, Douglas A.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleEffects of Age and Immune Dysfunction on the Cardiac Extracellular Matrix and Diastolic Functionen_US
dc.creatorAlwardt, Cory M.en_US
dc.contributor.authorAlwardt, Cory M.en_US
dc.date.issued2005en_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.abstractCardiomyopathies are often initiated by diastolic dysfunction, and treatment of diastolic dysfunction remains empirical with an emphasis on prevention. This dissertation focuses on the mechanism of cardiomyopathy and diastolic dysfunction during aging and immune dysfunction. The governing hypothesis is that altered cytokine release such as that seen during aging and immune dysfunction can lead to diastolic dysfunction and myocardial fibrosis. Our first study examined the role of aging and immunosenescence on the cardiac extracellular matrix (ECM) and left ventricular stiffness. We demonstrated age-related immune dysfunction, myocardial fibrosis, and diastolic dysfunction. We also found that exogenous dehydroepiandrosterone (DHEA), an adrenal steroid hormone popular due to its anti-aging effects, partially reversed these pathologies in aged mice. In this model, fibrosis and its reversal were associated with altered regulation of matrix metalloproteinases (MMP) and collagen cross-linking. We propose two mechanisms for the protective effects of DHEA: (1) a direct effect on cardiac fibroblasts, or (2) downstream effects of immune modulation. In the subsequent study, we found that DHEA is capable of directly altering cardiac fibroblasts, suggesting a mechanism for the effects of DHEA on cardiac function. Due to pleiotropic effects of DHEA, we decided to specifically target the immune system using T-cell receptor peptides during murine AIDS(mAIDS). Mice with mAIDS suffer from cardiomyopathy in the absence of myocarditis and opportunistic pathogens. We demonstrated that reversal of immune dysfunction in mAIDS was associated with reversal of myocardial fibrosis and ventricular stiffness. In conclusion, we have demonstrated age- and immune-related diastolic dysfunction that can be reversed by modulation of the T-cells of the immune system. Immune modulation should be further investigated as a therapeutic target to treat diastolic dysfunction during immune dysfunction. We also found that MMPs and collagen cross-linking are highly involved in extracellular matrix regulation in the models used in this dissertation.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectcardiomyopathyen_US
dc.subjectMMPen_US
dc.subjectmiceen_US
dc.subjectmAIDSen_US
dc.subjectDHEAen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairLarson, Douglas A.en_US
dc.contributor.committeememberSimon, Alexanderen_US
dc.contributor.committeememberLynch, Ronalden_US
dc.contributor.committeememberGregorio, Carolen_US
dc.contributor.committeememberBurt, Janisen_US
dc.identifier.proquest1128en_US
dc.identifier.oclc137354111en_US
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