In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland

Sánchez-Lemus, Enrique; Benický, Július; Pavel, Jaroslav; Saavedra, Juan M.

doi:10.1016/j.bbi.2009.04.012

Cited by 38 publications

(48 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since cortisol has anti-inflammatory effects, the reduced cortisol levels in PTSD could lead to a relatively increased inflammatory state in these patients. Consistent with this possibility, previous studies found that patients with PTSD also have increased expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α (Gill et al, 2008; Guo et al, 2012; Lindqvist et al, 2014; Rohleder et al, 2004; Sánchez-Lemus et al, 2009; van Zuiden et al, 2012). It has been hypothesized that increased inflammatory cytokines are involved in the pathogenesis of PTSD symptoms such as re-experiencing the traumatic event (Jones and Thomsen, 2013).…”

Section: Introductionsupporting

confidence: 60%

Candesartan ameliorates impaired fear extinction induced by innate immune activation

Quiñones

Maldonado

Velázquez

et al. 2016

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 hrs after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD.

show abstract

Section: Introductionsupporting

confidence: 60%

Candesartan ameliorates impaired fear extinction induced by innate immune activation

Quiñones

Maldonado

Velázquez

et al. 2016

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

show abstract

“…So it makes sense that losartan and candesartan which is well known to exert anti-inflammatory effects have the attenuating effect on iNOS expression. 35,36) In the present study, fimasartan also clearly suppressed induction of iNOS through down-regulation of its promoter activity and subsequent production of NO in LPS-stimulated macrophages. As mentioned above, Angiotensin II promotes the innate immune response, by mechanisms similar to those involved in the LPS effects, however, the possibility that AT1 receptor blockade was responsible for this inhibitory effect was eliminated by the finding macrophages treated with angiotensin II did not show significant effect on NO release compared with control cells, which imply that inhibitory effect of fimasartan on LPSinduced NO production is independent of AT1 receptor signaling (data not shown).…”

Section: )supporting

confidence: 65%

Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

Ryu

Shin

Cho

et al. 2013

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.Key words fimasartan; inflammation; nitric oxide; nuclear factor-kappa B; activator protein-1 Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. Hypertension patients have impaired functions of the endothelium, in which inflammation plays a key role.1) Angiotensin II is recognized as an important vascular pro-inflammatory factor in hypertension. Angiotensin II-driven vascular inflammation is considered the result of direct modulates on cytokine release and pro-inflammatory transcription factor including nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and angiotehsin II receptor blockers (ARBs) reduce the peripheral and cerebrovascular inflammation associated with this disease. 2,3)Anti-inflammatory effects of ARBs, first established in the peripheral vasculature, 4) were later demonstrated in the cerebral vasculature 5) and in stress-induced gastric ulcerations. 6)These observations suggest that ARBs may exert general antiinflammatory effects beyond those associated with cardiovascular and metabolic disease. 7) Thus, apart from being a major vasopressor effector of the renin-angiotensin system, ARBs are probably good candidate drugs for inflammation. 8)Since the important role of macrophages in inflammation, many investigations about ARBs (e.g., candesartan, losartan, telmisartan and valsartan) were performed in lipopolysaccharide (LPS)-induced macrophages.9-11) In fact, there are several physiological roles of angiotensin II type 1 (AT1) receptor in macrophages, such as positive regulation of peroxide production 12) and shift M1/M2 polarization balance. 13) However, in macrophages AT1a receptor expression level is reportedly low and AT1b receptor is not detected at all 14) and the most important feature of macrophages is that macrophages are widely distributed in the body and provide an immediate defense against foreign agents, such as lipopolysaccharide (LPS).15) Nitric oxide (NO), a potent pro-inflammatory mediator, is mainly produced by macrophages and acts as a cytotoxic agent during immune and inflammatory responses, which is...

show abstract

“…These observations suggest that ARBs may exert general anti-inflammatory effects beyond those associated with cardiovascular and metabolic disease. Evidence in support of this hypothesis was obtained in normotensive rodents in which candesartan reduced the peripheral and brain acute inflammation following systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) [17-19]. Anti-inflammatory effects of candesartan were also demonstrated in cultured circulating human monocytes expressing few AT 1 [20].…”

Section: Introductionmentioning

confidence: 99%

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Pang

Benický

Wang

et al. 2012

Journal of Hypertension

Self Cite

View full text Add to dashboard Cite

Objective Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPARγ activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARγ gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-κB activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-α, inhibitor of κB-α, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARγ target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARγ antagonism and PPARγ gene silencing. Anti-inflammatory effects of ARBs correlated with their PPARγ agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPARγ activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.

show abstract

In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland

Cited by 38 publications

References 82 publications

Candesartan ameliorates impaired fear extinction induced by innate immune activation

Candesartan ameliorates impaired fear extinction induced by innate immune activation

Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Contact Info

Product

Resources

About