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

McCarthy, Cameron G.; Goulopoulou, Styliani; Ogbi, Safia; Baban, Babak; Sullivan, Jennifer C.; Matsumoto, Takayuki; Webb, R.

doi:10.1093/cvr/cvv137

Cited by 148 publications

(139 citation statements)

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“…2 Previously, we observed that TLR9 was able to increase arterial blood pressure and cause endothelial dysfunction in rats with a normotensive background. 8 Nonetheless, the link between the innate immune system and the subsequent recruitment of the adaptive immune system in hypertensive rats remains unclear. Therefore, in this investigation, we hypothesized that inhibition of TLR9 with the lysosomotropic agent chloroquine (CQ), which has long been used as an inhibitor of endosomal TLR signaling, [11][12][13] would lower blood pressure and prevent the subsequent recruitment of immune cells to the vasculature in SHR.…”

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“…2,7 We have recently observed that mitochondrial DNA (mtDNA), a DAMP that activates TLR9, is increased in the circulation of spontaneously hypertensive rats (SHR). 8 Specifically, TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) dinucleotides and these are common in prokaryotic DNA and mtDNA, but not nuclear DNA. 9 Upon recognition of unmethylated CpG dinucleotides in Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats Cameron G. McCarthy, 1 Camilla F. Wenceslau, 1 Styliani Goulopoulou, 3 Babak Baban, 2 Takayuki Matsumoto, 4 and R. Clinton Webb 1…”

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Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

McCarthy

Goulopoulou

Baban

et al. 2016

AJHYPE

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Inappropriate immune system activation has been proposed as a unifying mechanism linking the 3 major organ systems that are dysregulated in the development and maintenance of hypertension-the cardiovascular system, the kidneys, and the autonomic nervous system. 1,2 However, the exact mechanisms that initiate this deleterious response, thereby contributing to further increases in blood pressure, are not well understood. 1,2 Although the participation of the adaptive immune system, and specifically T cells, in the pathogenesis of hypertension is not in question, 3,4 there are still gaps surrounding how it is signaled for involvement in the first place.Immune system recognition and response to danger is becoming apparent in a wide range of disease states, including cardiovascular diseases. 5 In this paradigm, the immune system responds to stimuli that it perceives as indicative of danger. 6 As such, molecules released from cell injury and death, called damage-associated molecular patterns (DAMPs), as well as pathogen-associated molecular patterns, signals to the immune system that a response is required. Normally, endogenous molecules are shielded from the immune system via compartmentalization within plasma membranes. However, when a cell dies or undergoes undue stress, these molecules can be released and are able to activate pattern recognition receptors on immune and nonimmune cells. 5 Toll-like receptors (TLR) are a class of innate immune system pattern recognition receptors that recognize and respond to DAMPs. 2,7 We have recently observed that mitochondrial DNA (mtDNA), a DAMP that activates TLR9, is increased in the circulation of spontaneously hypertensive rats (SHR). 8 Specifically, TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) dinucleotides and these are common in prokaryotic DNA and mtDNA, but not nuclear DNA. 9 Upon recognition of unmethylated CpG dinucleotides in BACKGROUNDInnate 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.

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Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

McCarthy

Goulopoulou

Baban

et al. 2016

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“…[1][2][3] Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, [10][11][12][13][14][15][16][17][18][19] a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.…”

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Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Matsumoto

Watanabe

Iguchi

et al. 2016

Biological & Pharmaceutical Bulletin

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We investigated the relationship between noradrenaline (NAd)-induced contractions, endothelial function, and hypertension in femoral arteries isolated from spontaneously hypertensive rats (SHR). In the femoral arteries of SHR, vs. age-matched control Wistar Kyoto (WKY) rats, contractions induced by NAd were increased. These effects were enhanced by endothelial denudation, which abolished the differences between the two groups. NAd-induced contractions were enhanced by nitric oxide (NO) synthase inhibition, and further increased by the blockade of endothelium-derived hyperpolarizing factor (EDHF). Conversely, NAd-induced contractions were inhibited by cyclooxygenase (COX) inhibition. In addition, in SHR arteries, acetylcholine-induced relaxation was reduced, and components of endothelium-derived factors were altered, such as increased COX-derived vasoconstrictor prostanoids, reduced EDHF, and preserved NO-mediated relaxation. In the femoral arteries of SHR, the production of prostanoids [6-keto prostaglandin (PG)F 1α (a metabolite of prostacyclin (PGI 2 ), PGE 2 , and PGF 2α ] and COX-2 protein were increased compared with that in WKY rats. By contrast, contractions induced by beraprost (a stable PGI 2 analogue), PGE 2 , and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAdinduced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels.Key words cyclooxygenase; endothelium; femoral artery; hypertension; contraction Hypertension is one of the most common chronic diseases in humans, 1) and hypertension-associated vascular complications such as stroke, heart failure, kidney diseases and peripheral arterial diseases are major sources of morbidity and mortality that exacerbate the quality of life.1-3) Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, 10-19) a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.Among endothelium-derived factors, nitric oxide (NO) is of the greatest importance for modulating vascular function. 20,21) However, other factors including endothelium-derived hyperpolarizing factor (EDHF) and cyclooxygenase (COX)-derived prostanoids can also modulate vascular tone. [22][23][24][25] Indeed, there are several reports suggesting that contraction induced by various substances including alpha-adrenoceptor ligands is enhanced by the inhibition of EDHF signaling 26) and enhanced 27) or suppressed 11,28,29) by COX signaling in various arteries under a (patho) physiological state. Because prostacyclin (PGI 2 ) serves as an endothelium-derived vasodilator and vasoconstrictor depending on the vessel t...

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“…7 In their study published in the current issue of American Journal of Hypertension, 8 these investigators extend their findings by testing a mechanism of intracellular TLR activation, particularly TLR9, in SHR hypertension. Chloroquine, a drug known as an effective antimalarial therapeutic agent, blocks endosomal maturation 9 by inhibiting vesicular acidification that is also required for TLR9 signaling.…”

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Toll-Like Receptors, Hypertension, and an Antimalarial Drug

Singh

2016

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The role of the immune system in the pathogenesis of hypertension is a growing area of research. Although the immune system had long been suspected to contribute to hypertension, only in the last decade have studies begun to define the roles of the participating immune cells and molecules involved in hypertension. [1][2][3][4] Toll-like receptors (TLRs) 5,6 are part of the innate immune system that recognize molecular patterns on various pathogens (pathogen-associated molecular patterns) and so called endogenous damage signals (damage-associated molecular patterns). These patterns may be proteins, lipids, carbohydrates, or nucleic acids. TLRs are expressed either on the cell surface or in intracellular endolysosomal compartment. Although the endogenous ligands of the TLRs that trigger hypertension have not been identified, disruption of TLR signaling has been shown to attenuate hypertension.In a study published last year in "Cardiovascular Research, " McCarthy et al. reported that intraperitoneal injection of a TLR9 inhibitory oligonucleotide ODN2088 in adult spontaneously hypertensive rats (SHR) decreased the systolic blood pressure, whereas injections of TLR9 agonist ODN2395 in normotensive rats increased the systolic blood pressure. 7 In their study published in the current issue of American Journal of Hypertension, 8 these investigators extend their findings by testing a mechanism of intracellular TLR activation, particularly TLR9, in SHR hypertension. Chloroquine, a drug known as an effective antimalarial therapeutic agent, blocks endosomal maturation 9 by inhibiting vesicular acidification that is also required for TLR9 signaling. 10 McCarthy et al. injected chloroquine in SHR to disrupt TLR9 signaling and measured expression of key molecular components of TLR signaling in mesenteric resistance vessels that significantly contribute to hypertension. The major finding of the study is that in young prehypertensive SHR (5 weeks old), disruption of intracellular TLR signaling by chloroquine decreased blood pressure. These findings are consistent with the authors' previous report as well as with the findings by Harwani et al. 11 demonstrating that the isolated splenocytes from prehypertensive SHR have an enhanced proinflammatory response to TLR 7/8 and 9 agonists in the presence of nicotine. In normotensive WistarKyoto rats, nicotine was anti-inflammatory. Moreover, in vivo infusion of nicotine in young prehypertensive SHR induces premature hypertension. 12 An important concept which evolves from this work is that the innate immune system is important in SHR hypertension. This concept is also shown to work in angiotensin II (Ang II) induced hypertension where priming of dendritic cells, a member of the innate immune system, by Ang II contributes to hypertension. 13 A second concept in this paper is the possible role of TLR adaptor protein MyD88. All TLRs, except intracellular TLR3, require MyD88 for signaling. Loss of MyD88 protein severely impairs TLR signaling and inflammatory responses. 14 In the study by Mc...

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

Abstract: 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.

Cited by 148 publications

References 59 publications

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

Toll-Like Receptors, Hypertension, and an Antimalarial Drug

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