Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

Cameron G. McCarthy, Camilla F. Wenceslau, Styliani Goulopoulou, Babak Baban, Takayuki Matsumoto, R. Clinton Webb

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

BACKGROUND: Innate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR.

METHODS: Initially, adult SHR and Wistar-Kyoto (WKY) rats (12 weeks old), as well as a group of young SHR (5 weeks old), were treated with CQ (40mg/kg/day) or vehicle (saline) via intraperitoneal injections for 21 days and then TLR9-myeloid differentiation primary response protein (MyD88) signaling proteins were assessed in mesenteric resistance arteries (MRA) via western blot. Subsequently, young SHR and WKY were treated from 5-8 weeks of age and then were allowed to mature without further treatment. Blood pressure was measured pretreatment, posttreatment, and after maturation, and immune cell recruitment to the vasculature was measured via flow cytometry after maturation.

RESULTS: In MRA from adult SHR, CQ increased the expression of MyD88-dependent proteins, whereas young SHR MRA exhibited a decrease. This inhibition was subsequently associated with suppression of blood pressure, as well as decreased counts of circulating T cells and vascular infiltrating leukocytes in SHR, when CQ was administered during the prehypertensive phase.

CONCLUSIONS: These data bring into question the participation of TLRs during the maintenance phase of hypertension and promote the exploration of innate immune system therapy during the critical developmental phase.

Original languageEnglish (US)
Pages (from-to)173-181
Number of pages9
JournalAmerican journal of hypertension
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2017

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Chloroquine
Inbred SHR Rats
Hypertension
Mesenteric Arteries
Myeloid Differentiation Factor 88
Immune System
Toll-Like Receptor 9
Blood Pressure
Inbred WKY Rats
Intraperitoneal Injections
Mitochondrial DNA
Innate Immunity
Blood Vessels
Flow Cytometry
Leukocytes
Western Blotting
Maintenance
T-Lymphocytes
Therapeutics

Keywords

  • Toll-like receptors.
  • blood pressure
  • hypertension
  • immune system

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats. / McCarthy, Cameron G.; Wenceslau, Camilla F.; Goulopoulou, Styliani; Baban, Babak; Matsumoto, Takayuki; Webb, R. Clinton.

In: American journal of hypertension, Vol. 30, No. 2, 01.02.2017, p. 173-181.

Research output: Contribution to journalArticle

McCarthy, Cameron G. ; Wenceslau, Camilla F. ; Goulopoulou, Styliani ; Baban, Babak ; Matsumoto, Takayuki ; Webb, R. Clinton. / Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats. In: American journal of hypertension. 2017 ; Vol. 30, No. 2. pp. 173-181.
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AB - BACKGROUND: Innate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR.METHODS: Initially, adult SHR and Wistar-Kyoto (WKY) rats (12 weeks old), as well as a group of young SHR (5 weeks old), were treated with CQ (40mg/kg/day) or vehicle (saline) via intraperitoneal injections for 21 days and then TLR9-myeloid differentiation primary response protein (MyD88) signaling proteins were assessed in mesenteric resistance arteries (MRA) via western blot. Subsequently, young SHR and WKY were treated from 5-8 weeks of age and then were allowed to mature without further treatment. Blood pressure was measured pretreatment, posttreatment, and after maturation, and immune cell recruitment to the vasculature was measured via flow cytometry after maturation.RESULTS: In MRA from adult SHR, CQ increased the expression of MyD88-dependent proteins, whereas young SHR MRA exhibited a decrease. This inhibition was subsequently associated with suppression of blood pressure, as well as decreased counts of circulating T cells and vascular infiltrating leukocytes in SHR, when CQ was administered during the prehypertensive phase.CONCLUSIONS: These data bring into question the participation of TLRs during the maintenance phase of hypertension and promote the exploration of innate immune system therapy during the critical developmental phase.

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