Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats

Cameron G. McCarthy, Camilla F. Wenceslau, Styliani Goulopoulou, Safia Ogbi, Babak Baban, Jennifer C Sullivan, Takayuki Matsumoto, R Clinton Webb

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Aims Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. Methods and results We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic 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 increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Conclusion Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

Original languageEnglish (US)
Pages (from-to)119-130
Number of pages12
JournalCardiovascular Research
Volume107
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Toll-Like Receptor 9
Inbred SHR Rats
Mitochondrial DNA
Blood Vessels
Blood Pressure
Immune System
Deoxyribonucleases
Deoxyribonuclease I
p38 Mitogen-Activated Protein Kinases
Prostaglandin-Endoperoxide Synthases
Oligonucleotides
Biological Availability
Acetylcholine
Reactive Oxygen Species
Norepinephrine
Arterial Pressure
Nitric Oxide
Cardiovascular Diseases
Arteries
Hypertension

Keywords

  • Hypertension
  • Innate immunity
  • Mitochondrial DNA
  • Toll-like receptor 9
  • Vascular dysfunction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. / McCarthy, Cameron G.; Wenceslau, Camilla F.; Goulopoulou, Styliani; Ogbi, Safia; Baban, Babak; Sullivan, Jennifer C; Matsumoto, Takayuki; Webb, R Clinton.

In: Cardiovascular Research, Vol. 107, No. 1, 01.07.2015, p. 119-130.

Research output: Contribution to journalArticle

McCarthy, Cameron G. ; Wenceslau, Camilla F. ; Goulopoulou, Styliani ; Ogbi, Safia ; Baban, Babak ; Sullivan, Jennifer C ; Matsumoto, Takayuki ; Webb, R Clinton. / Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. In: Cardiovascular Research. 2015 ; Vol. 107, No. 1. pp. 119-130.
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abstract = "Aims Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. Methods and results We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic 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 increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Conclusion Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.",
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T1 - Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats

AU - McCarthy, Cameron G.

AU - Wenceslau, Camilla F.

AU - Goulopoulou, Styliani

AU - Ogbi, Safia

AU - Baban, Babak

AU - Sullivan, Jennifer C

AU - Matsumoto, Takayuki

AU - Webb, R Clinton

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N2 - Aims Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. Methods and results We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic 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 increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Conclusion Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

AB - Aims Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. Methods and results We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic 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 increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. Conclusion Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

KW - Hypertension

KW - Innate immunity

KW - Mitochondrial DNA

KW - Toll-like receptor 9

KW - Vascular dysfunction

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U2 - 10.1093/cvr/cvv137

DO - 10.1093/cvr/cvv137

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