Vascular Dysfunction following Polymicrobial Sepsis: Role of Pattern Recognition Receptors

Ehrentraut, Stefan; Dörr, Anne; Ehrentraut, Heidi; Lohner, Ralph; Lee, Sunhee; Hoeft, Andreas; Baumgarten, Georg; Knuefermann, Pascal; Boehm, Olaf; Meyer, Rainer

doi:10.1371/journal.pone.0044531

Cited by 14 publications

(26 citation statements)

References 39 publications

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“…Thus, the sensitivity of the arterial wall to LTA will influence the blood pressure in the situation of a TLR2-dependent inflammation. Recently it has been shown that LTA application to isolated blood vessels can even improve vascular contractility [11]. This effect may support the stability of SABP observed here.…”

Section: Discussionsupporting

confidence: 89%

TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

et al. 2013

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BackgroundBacteria such as Staphylococcus aureus induce myocardial dysfunction in vivo. To rectify conflicting evidence about the role of TLR2 signaling and cardiac dysfunction, we hypothesized that the specific TLR2 agonist purified lipoteichoic acid (LTA) from S. aureus contributes to cardiac dysfunction in vitro and in vivo.MethodsWildtype (WT-) and TLR2-deficient (TLR2-D) mice were challenged with LTA and in comparison with equivalent doses of lipopolysaccharide (LPS) and CpG-oligodeoxynucleotide (CpG-ODN). TLR2-expression, NFκB as well as cytokine response were determined. Sarcomere shortening of isolated cardiomyocytes was analyzed in vitro and cardiac function in vivo after stimulation with LTA.ResultsLTA induced up-regulation of TLR2 mRNA, activation of NFκB and cytokine expression within 2–6 h in WT-, but not in TLR2-D hearts. Cytokines were also elevated in the serum. LPS and CpG-ODN induced a more severe cardiac inflammation. In vitro incubation of cardiomyocytes with LTA reduced sarcomere shortening via NO at stimulation frequencies ≤ 8 Hz only in WT cells. However, hemodynamic parameters in vivo were not affected by LTA challenge.ConclusionsLTA induced cardiac inflammation was relatively weak and sarcomere shortening was reduced only below physiological heart rates. This may explain the apparent contradiction between the in vivo and in vitro LTA effects.

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Section: Discussionsupporting

confidence: 89%

TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

et al. 2013

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“…Oka et al (68) demonstrated that mtDNA that escapes from autophagy leads to TLR9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. TLR9 also plays a key role in vascular dysfunction observed in experimental models of polymicrobial sepsis (19). In the same model, Lohner et al (52) demonstrated that TLR9 elicits cardiac inflammation and heart failure.…”

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confidence: 99%

Toll-like receptor 9 plays a key role in the autonomic cardiac and baroreflex control of arterial pressure

Rodrigues

Silva

Hott

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.

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“…Sepsis is a major clinical problem with more than a 40% mortality rate [1], [3]. Sepsis is the most important cause of morbidity and mortality in intensive care units (ICUs), and about 60% of patients admitted to the ICU have cardiac dysfunction [2], [3], [4], [23].…”

Section: Discussionmentioning

confidence: 99%

“…Sepsis is the No.1 cause of morbidity and mortality in intensive care units (ICUs), and about 60% of patients admitted to the ICU have cardiac dysfunction [2], [3], [4]. When accompanied by heart dysfunction, survival for sepsis is only 30% [1], [2].…”

Section: Introductionmentioning

confidence: 99%

“…However, the mortality rate is nearly 40% in an advanced aged patient under severe sepsis in spite of aggressive treatment [1], [2]. Cardiac dysfunction plays a critical role in the high morbidity and mortality of this condition [2], [3], [4]. Therefore, it is urgent to elucidate the mechanisms by which sepsis modulates cardiac dysfunction and generate more efficient ways to improve the prognosis.…”

Section: Introductionmentioning

confidence: 99%

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β-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38

Yan

Denney

et al. 2016

Biochemistry and Biophysics Reports

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Sepsis is an exaggerated systemic inflammatory response to persistent bacteria infection with high morbidity and mortality rate clinically. β-arrestin 2 modulates cell survival and cell death in different systems. However, the effect of β-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known. Here, we show that β-arrestin 2 overexpression significantly enhances animal survival following cecal ligation and puncture (CLP)-induced sepsis. Importantly, overexpression of β-arrestin 2 in mice prevents CLP-induced cardiac dysfunction. Also, β-arrestin 2 overexpression dramatically attenuates CLP-induced myocardial gp130 and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels following CLP. Therefore, β-arrestin 2 prevents CLP-induced cardiac dysfunction through gp130 and p38. These results suggest that modulation of β-arrestin 2 might provide a novel therapeutic approach to prevent cardiac dysfunction in patients with sepsis.

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Vascular Dysfunction following Polymicrobial Sepsis: Role of Pattern Recognition Receptors

Cited by 14 publications

References 39 publications

TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo

Toll-like receptor 9 plays a key role in the autonomic cardiac and baroreflex control of arterial pressure

β-arrestin 2 attenuates cardiac dysfunction in polymicrobial sepsis through gp130 and p38

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