Vascular Kinin B1 and B2 Receptors Determine Endothelial Dysfunction through Neuronal Nitric Oxide Synthase

Mesquita, Thássio; Campos-Mota, Gianne P.; Lemos, Virgı́nia S.; Cruz, Jáder Santos; Jesus, Itamar Couto Guedes de; Camargo, Enilton A.; Pesquero, Jorge L.; Pesquero, João Bosco; Capettini, Luciano dos Santos Aggum; Lauton-Santos, Sandra

doi:10.3389/fphys.2017.00228

Cited by 8 publications

(4 citation statements)

References 62 publications

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“…The absence of inducible B1R reduces the mice survival during P. chabaudi infection (Fig. 2), which is probably related to the endothelial vascular dysfunction associated to changes in NO production and excessive ROS generation [45]. In inflammation models, B1R are involved in cell protection effects [30, 36, 46].…”

Section: Discussionmentioning

confidence: 99%

Malaria infection promotes a selective expression of kinin receptors in murine liver

Ventura

Carvalho

Barros

et al. 2019

Malar J

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Background Malaria represents a worldwide medical emergency affecting mainly poor areas. Plasmodium parasites during blood stages can release kinins to the extracellular space after internalization of host kininogen inside erythrocytes and these released peptides could represent an important mechanism in liver pathophysiology by activation of calcium signaling pathway in endothelial cells of vertebrate host. Receptors (B1 and B2) activated by kinins peptides are important elements for the control of haemodynamics in liver and its physiology. The aim of this study was to identify changes in the liver host responses (i.e. kinin receptors expression and localization) and the effect of ACE inhibition during malaria infection using a murine model. Methods Balb/C mice infected by Plasmodium chabaudi were treated with captopril, an angiotensin I-converting enzyme (ACE) inhibitor, used alone or in association with the anti-malarial chloroquine in order to study the effect of ACE inhibition on mice survival and the activation of liver responses involving B1R and B2R signaling pathways. The kinin receptors (B1R and B2R) expression and localization was analysed in liver by western blotting and immunolocalization in different conditions. Results It was verified that captopril treatment caused host death during the peak of malaria infection (parasitaemia about 45%). B1R expression was stimulated in endothelial cells of sinusoids and other blood vessels of mice liver infected by P. chabaudi . At the same time, it was also demonstrated that B1R knockout mice infected presented a significant reduction of survival. However, the infection did not alter the B2R levels and localization in liver blood vessels. Conclusions Thus, it was observed through in vivo studies that the vasodilation induced by plasma ACE inhibition increases mice mortality during P. chabaudi infection. Besides, it was also seen that the anti-malarial chloroquine causes changes in B1R expression in liver, even after days of parasite clearance. The differential expression of B1R and B2R in liver during malaria infection may have an important role in the disease pathophysiology and represents an issue for clinical treatments.

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Section: Discussionmentioning

confidence: 99%

Malaria infection promotes a selective expression of kinin receptors in murine liver

Ventura

Carvalho

Barros

et al. 2019

Malar J

Self Cite

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“…Actually, B2R is reputed to be an eNOS activator, but B1R is also capable of similar effects because these two receptors share the same signaling pathways [4][5][6]. Various researches have shown either negative regulation of eNOS transcription in the absence of B1R, a co-localization of B1R and eNOS, or new potential transduction pathways that enable the activation of eNOS by B1R [52][53][54][55]. In addition, B1R is capable of activating the PI3/Akt pathway, which phosphorylates eNOS in serine 1177 [56][57][58].…”

Section: Discussionmentioning

confidence: 99%

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability

et al. 2020

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Background: In sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. VE-cadherin, an adherens junction protein, is the gatekeeper of endothelial cohesion. Kinins, released during sepsis, induce vascular leakage and vasodilation. They act via two G-protein coupled receptors: B1 (B1R) and B2 (B2R). B1R is inducible in the presence of pro-inflammatory cytokines, endotoxins or after tissue injury. It acts at a later stage of sepsis and elicits a sustained inflammatory response. The aim of our study was to investigate the relationships between B1R and VE-cadherin destabilization in vivo in a later phase of sepsis. Methods: Experimental, prospective study in a university research laboratory. We used a polymicrobial model of septic shock by cecal ligation and puncture in C57BL6 male mice or C57BL6 male mice that received a specific B1R antagonist (R-954). We studied the influence of B1R on sepsis-induced vascular permeability 30 h after surgery for several organs, and VE-cadherin expression in the lung and kidneys by injecting R-954 just before surgery. The 96-h survival was determined in mice without treatment or in animals receiving R-954 as a "prophylactic" regimen (a subcutaneous injection of 200 µg/kg, prior to CLP and 24 h after CLP), or as a "curative" regimen (injection of 100 µg/kg at H6, H24 and H48 post-surgery). Results: B1R inactivation helps to maintain MAP above 65 mmHg but induces different permeability profiles depending on whether or not organ perfusion is autoregulated. In our model, VE-cadherin was destabilized in vivo during septic shock. At a late stage of sepsis, the B1R blockade reduced the VE-cadherin disruption by limiting eNOS activation. The survival rate for mice that received R-954 after sepsis induction was higher than in animals that received an antagonist as a prophylactic treatment. Conclusions: B1R antagonizing reduced mortality in our model of murine septic shock by limiting the vascular permeability induced by VE-cadherin destabilization through maintenance of the macrohemodynamics, consequently limiting organ dysfunctions.

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“…For NO measurement, the cells were seeded at a density of 5 × 10 4 cells/well in a 24-well plate and incubated in EGM-2 medium for 24 h. After the medium was removed, the cells were rinsed twice with phosphatebuffered saline (PBS). Thereafter, the cells were incubated with 1 μM hesperidin, 1 μM capsaicin, 1 μM hesperidin analogues, or 1 μM Ang (1−7) in a phenol red-free EBM-2 medium (CC-3129, Lonza Co.) for 2 h. For inhibitor experiments, HUVECs were incubated with 1 μM hesperidin in the presence or absence of either A-779 (MasR antagonist, 10 1 μM); ICI 182780 (estrogen receptor (ER) antagonist, 11 1 μM); PD-123319 (AT 2 R antagonist, 12 1 μM); icatibant (BK 2 R antagonist, 13 1 μM); capsazepine (TRPV1 antagonist, 14 10 μM); KN-62 (CaMKII inhibitor, 15 10 μM); or L-NMMA (eNOS inhibitor, 16 100 μM) for 2 h. After incubation, the medium was collected and centrifuged at 1,000g for 15 min at 4 °C, and the supernatant was subjected to NO measurements using the NO assay-FX kit, according to the manufacturer's protocol. For intracellular Ca 2+ measurement, the cells seeded at 1.0 × 10 4 cells/ well in a 96-well plate were used.…”

Section: T H Imentioning

confidence: 99%

Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells

Gao

Nakamura

Asaba

et al. 2022

J. Agric. Food Chem.

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Here, the mechanism of vasorelaxant Mas receptor (MasR) expression elevated by hesperidin in spontaneously hypertensive rats was investigated in human umbilical vein endothelial cells (HUVECs). HUVECs were cultured with 1 μM hesperidin for 2 h, following the measurements of nitric oxide (NO) production and vasomotor-related receptors’ expression. Hesperidin significantly promoted NO production (224.1 ± 18.3%, P < 0.01 vs control) in the HUVECs. Only the MasR expression was upregulated (141.2 ± 12.5%, P < 0.05 vs control), whereas a MasR antagonist did not alter the hesperidin-induced NO production. When a transient receptor potential vanilloid 1 (TRPV1) was knocked down by silencing RNA or Ca2+/calmodulin-dependent kinase II (CaMKII) and p38 mitogen-activated protein kinase (p38 MAPK) were inhibited, the increased MasR expression by hesperidin was abrogated. The inhibitions of CaMKII and endothelial NO synthase (eNOS) abolished the hesperidin-induced NO production. The structure–activity relationship analysis of flavonoids demonstrated that the B ring of the twisted flavonoid skeleton with a hydroxy group at the 3′ position was a crucial factor for TRPV1 stimulation. Taken together, it was demonstrated that hesperidin may stimulate TRPV1-mediated cascades, leading to the activation of two signaling axes, CaMKII/p38 MAPK/MasR expression and CaMKII/eNOS/NO production in HUVECs.

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Vascular Kinin B1 and B2 Receptors Determine Endothelial Dysfunction through Neuronal Nitric Oxide Synthase

Cited by 8 publications

References 62 publications

Malaria infection promotes a selective expression of kinin receptors in murine liver

Malaria infection promotes a selective expression of kinin receptors in murine liver

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability

Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells

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