Persistent Link:
http://hdl.handle.net/10150/195040
Title:
Immune Basis of Arterial Hypertension
Author:
Vazquez, Randy
Issue Date:
2010
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:
A better understanding of these structural changes that occur before Hypertension (HTN) could ultimately result in a treatment that can prevent or reverse this disease state before its onset. T cells have been shown essential for the development of HTN. The aim of these murine studies was to investigate the role of the T-helper CD4⁺ lymphocytes in initiating vascular remodeling and HTN in the absence of an increased mechanical load and to investigate the role of T-helper 17 (Th17) CD4⁺ lymphocyte initiating vascular remodeling and HTN by stimulating Lysyl Oxidase (LOX). LOX is known to cross-link collagen and elastin and. Excess synthesis of collagen and elastin results in a stiffer artery and hypertension. We established L-NAME-induce HTN in wild type (WT) mice. CD4⁺ splenic lymphocytes were isolated from these mice and adoptively transferred into naïve syngeneic severe combined immunodeficient (SCID) mice. The SCID mice receiving these cells became hypertensive. Cytokine analysis demonstrated an increase in both Th1 and Th17 cytokine in HTN donor mice and of lymphocytes in the aortic infiltrates of the HTN recipient mice. The increased collagen and LOX expression in recipient mice suggest that the adoptively transfer CD4⁺ lymphocytes are associated with vascular extracellular matrix remodeling. Furthermore we examined the role of Th17 lymphocyte in aortic LOX regulation in Angiotensin II-induced hypertension. The Increase in blood pressure and Velocity Time Integral (VTI) was measured in WT Angiotensin II treated mice whereas no change was detected in the Th17 deficient (RORT KO) Angiotensin II treated group. When compared to the control group the WT group infused with Angiotensin II had higher LOX protein expression, LOX fluorescent Immunohistochemical stain and LOX activity. This group also had increased hydroxyproline levels, collagen stain, hyperplasia and aortic thickening. In contrast, the Th17 deficient mice Angiotensin II treated group had no changes in these parameters. The results provide evidence that IL-17 mediates Angiotensin II-induced hypertension and vascular dysfunction by the overstimulation of LOX. Potentially targeting T17 cells will allow for a drug-specific therapeutic approach and delay the progression of hypertension pathology.
Type:
text; Electronic Dissertation
Keywords:
Angiotensin II; Extracellular Matrix; Hypertension; L-NAME; Lysyl Oxidase (LOX); T-helper (Th)-17 lymphocytes
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Nutritional Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Larson, Douglas F.
Committee Chair:
Watson, Ronald R.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleImmune Basis of Arterial Hypertensionen_US
dc.creatorVazquez, Randyen_US
dc.contributor.authorVazquez, Randyen_US
dc.date.issued2010en_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.abstractA better understanding of these structural changes that occur before Hypertension (HTN) could ultimately result in a treatment that can prevent or reverse this disease state before its onset. T cells have been shown essential for the development of HTN. The aim of these murine studies was to investigate the role of the T-helper CD4⁺ lymphocytes in initiating vascular remodeling and HTN in the absence of an increased mechanical load and to investigate the role of T-helper 17 (Th17) CD4⁺ lymphocyte initiating vascular remodeling and HTN by stimulating Lysyl Oxidase (LOX). LOX is known to cross-link collagen and elastin and. Excess synthesis of collagen and elastin results in a stiffer artery and hypertension. We established L-NAME-induce HTN in wild type (WT) mice. CD4⁺ splenic lymphocytes were isolated from these mice and adoptively transferred into naïve syngeneic severe combined immunodeficient (SCID) mice. The SCID mice receiving these cells became hypertensive. Cytokine analysis demonstrated an increase in both Th1 and Th17 cytokine in HTN donor mice and of lymphocytes in the aortic infiltrates of the HTN recipient mice. The increased collagen and LOX expression in recipient mice suggest that the adoptively transfer CD4⁺ lymphocytes are associated with vascular extracellular matrix remodeling. Furthermore we examined the role of Th17 lymphocyte in aortic LOX regulation in Angiotensin II-induced hypertension. The Increase in blood pressure and Velocity Time Integral (VTI) was measured in WT Angiotensin II treated mice whereas no change was detected in the Th17 deficient (RORT KO) Angiotensin II treated group. When compared to the control group the WT group infused with Angiotensin II had higher LOX protein expression, LOX fluorescent Immunohistochemical stain and LOX activity. This group also had increased hydroxyproline levels, collagen stain, hyperplasia and aortic thickening. In contrast, the Th17 deficient mice Angiotensin II treated group had no changes in these parameters. The results provide evidence that IL-17 mediates Angiotensin II-induced hypertension and vascular dysfunction by the overstimulation of LOX. Potentially targeting T17 cells will allow for a drug-specific therapeutic approach and delay the progression of hypertension pathology.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAngiotensin IIen_US
dc.subjectExtracellular Matrixen_US
dc.subjectHypertensionen_US
dc.subjectL-NAMEen_US
dc.subjectLysyl Oxidase (LOX)en_US
dc.subjectT-helper (Th)-17 lymphocytesen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineNutritional Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorLarson, Douglas F.en_US
dc.contributor.chairWatson, Ronald R.en_US
dc.contributor.committeememberLarson, Douglas F.en_US
dc.contributor.committeememberBurd, Randyen_US
dc.contributor.committeememberThomson, Cynthiaen_US
dc.identifier.proquest11222en_US
dc.identifier.oclc752261066en_US
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