Toll-like receptor 9 contributes to vascular dysfunction in hypertension

Hdl Handle:
http://hdl.handle.net/10675.2/611568
Title:
Toll-like receptor 9 contributes to vascular dysfunction in hypertension
Authors:
McCarthy, Cameron
Abstract:
Inappropriate immune system activation is common in hypertension; however, the exact mechanisms by which this occurs are not well understood. Innate immune system recognition and response to damage-associated molecular patterns (DAMPs) is becoming an increasingly accepted mechanism. Mitochondrial DNA (mtDNA) is a DAMP that is recognized by Toll-like receptor (TLR)9, and it is elevated in the circulation of spontaneously hypertensive rats (SHR). Therefore, we hypothesized that (1) inhibition of TLR9 in SHR with a TLR9 antagonist (ODN2088) or TLR9 inhibitor (chloroquine) would lower blood pressure and improve vascular function and that (2) treatment of normotensive rats with a TLR9 agonist (ODN2395) would cause vascular dysfunction and increase blood pressure. Both ODN2088 and chloroquine lowered high blood pressure in SHR and treatment with chloroquine also improved cyclooxygenase-dependent endothelial function and prevented the full recruitment of the adaptive immune system in SHR. On the other hand, treatment of normotensive rats with ODN2395 increased blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to cyclooxygenase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. In conclusion, these findings support the involvement of the innate immune system pattern recognition receptor TLR9 in the pathogenesis and maintenance of hypertension. Specifically, circulating mtDNA may activate TLR9 and contribute to high blood pressure and endothelial dysfunction in SHR.
Affiliation:
Department of Physiology
Issue Date:
Mar-2016
URI:
http://hdl.handle.net/10675.2/611568
Type:
Dissertation
Appears in Collections:
Theses and Dissertations; Department of Physiology Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorMcCarthy, Cameronen
dc.date.accessioned2016-06-02T14:07:11Zen
dc.date.available2016-06-02T14:07:11Zen
dc.date.issued2016-03en
dc.identifier.urihttp://hdl.handle.net/10675.2/611568en
dc.description.abstractInappropriate immune system activation is common in hypertension; however, the exact mechanisms by which this occurs are not well understood. Innate immune system recognition and response to damage-associated molecular patterns (DAMPs) is becoming an increasingly accepted mechanism. Mitochondrial DNA (mtDNA) is a DAMP that is recognized by Toll-like receptor (TLR)9, and it is elevated in the circulation of spontaneously hypertensive rats (SHR). Therefore, we hypothesized that (1) inhibition of TLR9 in SHR with a TLR9 antagonist (ODN2088) or TLR9 inhibitor (chloroquine) would lower blood pressure and improve vascular function and that (2) treatment of normotensive rats with a TLR9 agonist (ODN2395) would cause vascular dysfunction and increase blood pressure. Both ODN2088 and chloroquine lowered high blood pressure in SHR and treatment with chloroquine also improved cyclooxygenase-dependent endothelial function and prevented the full recruitment of the adaptive immune system in SHR. On the other hand, treatment of normotensive rats with ODN2395 increased blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to cyclooxygenase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. In conclusion, these findings support the involvement of the innate immune system pattern recognition receptor TLR9 in the pathogenesis and maintenance of hypertension. Specifically, circulating mtDNA may activate TLR9 and contribute to high blood pressure and endothelial dysfunction in SHR.en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectInnate Immunityen
dc.subjectMitochondrial DNAen
dc.subjectVascular Dysfunctionen
dc.subjectHypertensionen
dc.titleToll-like receptor 9 contributes to vascular dysfunction in hypertensionen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorWebb, R. Clintonen
dc.description.committeeBelin de Chantemèle, Eric; Bollag, Wendy; Caldwell, R. William; Ergul, Adviyeen
dc.description.degreeDoctor of Philosophy with a Major in Physiologyen
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