FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model

Horewicz, Verônica Vargas; Crestani, Sandra; Rezende, Edir; Assreuy, Jamil

doi:10.1016/j.ejphar.2014.11.026

Cited by 17 publications

(15 citation statements)

References 31 publications

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“…31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis. 31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Chen

et al. 2019

J Cellular Molecular Medi

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The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast‐related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)‐1β and TNF‐α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL‐ and lipopolysaccharide (LPS)‐induced osteoclast differentiation and maturation in vitro and alleviates LPS‐induced osteolysis in animal models. WKYMVm down‐regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF‐kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.

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“…31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis. 31,32 Other FPR2 agonists have previously been reported to inhibit osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Chen

et al. 2019

J Cellular Molecular Medi

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“…Specifically, the lipid mediator FPR2-selective agonist, lipoxin A4 (LxA4), induces endothelium-dependent relaxation in preconstricted rat aorta, mesenteric arteries, and human omental veins but not arteries [19,20]. On the contrary, other studies demonstrated that LxA4 selectively activates FPR2 to induce concentration-dependent contractions via reactive oxygen species production and RhoA/Rho kinase-dependent pathway in the rat aorta [21][22][23]. Similarly, intravenous administration of LxA4 in vivo dose-dependently constricted mesenteric arterial bed [35].…”

Section: Discussionmentioning

confidence: 99%

“…The impact of FPR agonists on the regulation of vascular tone under physiological condition remains unclear and contradicting. For example, several studies reported that the lipid mediator FPR2-selective agonist, lipoxin A4 (LxA4) is co-currently a vasodilator [19,20] and vasoconstrictor [21][22][23]. Given the profound beneficial effects of small-molecule-based FPR agonists in the heart, particularly those exhibiting selectivity away from calcium mobilization, their impact on vascular tone is worthy of investigation.…”

Section: Introductionmentioning

confidence: 99%

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

Marshall

Qin

Jelinic

et al. 2020

IJMS

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The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.

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“…Beyond a peptide that triggers immune responses, WKYMVm and its analogues also play a role in vascular dysfunction. WKYMVm reverses vascular hyporeactivity to phenylephrine induced by LPS in mouse aorta through decreasing the production of nitric oxide . LL‐37, another FPR agonist, was reported to change smooth muscle contractility via increasing the levels of endothelium‐dependent factors .…”

Section: Introductionmentioning

confidence: 99%

“…WKYMVm reverses vascular hyporeactivity to phenylephrine induced by LPS in mouse aorta through decreasing the production of nitric oxide. 15 LL-37, another FPR agonist, was reported to change smooth muscle contractility via increasing the levels of endotheliumdependent factors. 16 As all these previous studies are limited to investigating the functions of FPR agonists on large vessels, the WKYMVminduced alterations in microvasculature remain unknown.…”

mentioning

confidence: 99%

Critical role for PI3Kγ-dependent neutrophil reactive oxygen species in WKYMVm-induced microvascular hyperpermeability

Zhou

et al. 2019

Journal of Leukocyte Biology

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PI3K has been indicated in regulating microvascular permeability changes during inflammation. However, its role in neutrophil‐driven microvascular leakage in acute inflammation remains unclear. Using intravital microscopy in mice, we examined the role of PI3Kγ and PI3Kδ in formyl peptide WKYMVm‐ and chemokine CXCL2‐induced permeability changes and assessed simultaneously neutrophil adhesion and emigration in post‐capillary venules of murine cremaster muscle. We found a PI3Kγ‐specific mechanism in WKYMVm‐induced but not CXCL2‐induced microvascular hyperpermeability. The increased microvascular permeability triggered by WKYMVm was not entirely due to neutrophil adhesion and emigration in cremasteric microvasculature in different PI3K transgenic mouse strains. The PI3Kγ‐specific hyperpermeability was neutrophil‐mediated as this was reduced after depletion of neutrophils in mouse circulation. Chimeric mice with PI3Kγ‐deficient neutrophils but wild‐type endothelium also showed reduced hyperpermeability. Furthermore, we found that the catalytic function of PI3Kγ was required for reactive oxygen species (ROS) generation in neutrophils stimulated with WKYMVm. Pharmacological scavenging PI3Kγ‐dependent ROS in the tissue eliminated the discrepancy in hyperpermeability between different PI3K transgenic mice and alleviated WKYMVm‐induced microvascular leakage in all mouse strains tested. In conclusion, our study uncovers the critical role for PI3Kγ‐dependent ROS generation by neutrophils in formyl peptide‐induced microvascular hyperpermeability during neutrophil recruitment.

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FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model

Cited by 17 publications

References 31 publications

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

Critical role for PI3Kγ-dependent neutrophil reactive oxygen species in WKYMVm-induced microvascular hyperpermeability

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