Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

Debreczeni, Márta L.; Németh, Zsuzsanna; Kajdácsi, Erika; Farkas, Henriette; Cervenak, László

doi:10.1007/s12016-021-08851-8

Cited by 17 publications

(13 citation statements)

References 251 publications

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“…The barrier function of the endothelium is tightly regulated, and its failure can lead to chronic inflammation as well as an increased metastatic risk 1 . Weakening of endothelial cell–cell (junctional) adhesion can be triggered by cytokines, growth factors, protease‐activated receptor (also known as thrombin receptor) agonists, and several other molecules reviewed in Debreczeni et al 2 Under resting condition, VE‐cadherin‐based linear adherens junctions are stabilized by circumferential actin bundles (CAB). Permeability‐increasing agents induce the reorganization of the actin cytoskeleton and the formation of radial stress fibers (RSF), which is accompanied by gap formation between two endothelial cells 3 .…”

Section: Introductionmentioning

confidence: 99%

BRAF increases endothelial cell stiffness through reorganization of the actin cytoskeleton

et al. 2022

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The dynamics of the actin cytoskeleton and its connection to endothelial cellcell junctions determine the barrier function of endothelial cells. The proper regulation of barrier opening/closing is necessary for the normal function of vessels, and its dysregulation can result in chronic and acute inflammation leading to edema formation. By using atomic force microscopy, we show here that thrombin-induced permeability of human umbilical vein endothelial cells, associated with actin stress fiber formation, stiffens the cell center. The depletion of the MEK/ERK kinase BRAF reduces thrombin-induced permeability prevents stress fiber formation and cell stiffening. The peripheral actin ring becomes stabilized by phosphorylated myosin light chain, while cofilin is excluded from the cell periphery. All these changes can be reverted by the inhibition of ROCK, but not of the MEK/ERK module. We propose that the balance between the binding of cofilin and myosin to F-actin in the cell periphery, which is regulated by the activity of ROCK, determines the local dynamics of actin reorganization, ultimately driving or preventing stress fiber formation.

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Section: Introductionmentioning

confidence: 99%

BRAF increases endothelial cell stiffness through reorganization of the actin cytoskeleton

et al. 2022

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“…Unabated generation of bradykinin, resulting from insufficient C1-INH regulation of factor XIIa and kallikrein, leads to angioedema. Plasma kallikrein cleaves factor XIIa, leading to activation of the complement cascade; activation of complement results in the cleavage of C5 (to the anaphylatoxin C5a) and formation of the complement fragment C4a, which increases endothelial permeability ( 17 ). Cytokines can also affect endothelial permeability, with proinflammatory cytokines (e.g., interleukin [IL]-1, IL-4, IL-6, IL-8, IL-13) increasing permeability and anti-inflammatory cytokines (e.g., IL-1Ra, IL-10) inhibiting permeability ( 17 ).…”

Section: Pathways Of Importance In Haementioning

confidence: 99%

“…Plasma kallikrein cleaves factor XIIa, leading to activation of the complement cascade; activation of complement results in the cleavage of C5 (to the anaphylatoxin C5a) and formation of the complement fragment C4a, which increases endothelial permeability ( 17 ). Cytokines can also affect endothelial permeability, with proinflammatory cytokines (e.g., interleukin [IL]-1, IL-4, IL-6, IL-8, IL-13) increasing permeability and anti-inflammatory cytokines (e.g., IL-1Ra, IL-10) inhibiting permeability ( 17 ). While evidence supports a key role of the bradykinin B 2 (B2) receptor in angioedema, upregulation of the bradykinin B 1 (B1) receptor during stress, trauma, or infection may influence susceptibility to angioedema, and prolonged B1 signaling may be involved in sustaining swelling during an HAE attack ( 16 , 18 ).…”

Section: Pathways Of Importance In Haementioning

confidence: 99%

Treatment of hereditary angioedema—single or multiple pathways to the rescue

Valerieva

Longhurst

2022

Front. Allergy

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Hereditary angioedema (HAE) is a rare disease caused by mutations in the SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways via direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B2 receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.

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“…[ 68 ] Bradykinin binds to the B2 receptor to stimulate the release of nitric oxide, prostaglandin I2, and endothelium-dependent hyperpolarizing factor, resulting in a strong vasodilation effect. [ 69 ] Although bradykinin’s vasodilatory effect benefits the heart, its accumulation also leads to angioedema. [ 70 ] Because neprilysin inhibition involves variable peptides and many pathways, the precise mechanisms of the ventricular arrhythmia reduction effects of neprilysin inhibition are complex and poorly defined.…”

Section: Possible Mechanisms Underlying the Antiarrhythmic Effect Of ...mentioning

confidence: 99%

A narrative review on sacubitril/valsartan and ventricular arrhythmias

Wei

Zhang²,

Zhang³

et al. 2022

Medicine

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Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients.

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Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

Cited by 17 publications

References 251 publications

BRAF increases endothelial cell stiffness through reorganization of the actin cytoskeleton

BRAF increases endothelial cell stiffness through reorganization of the actin cytoskeleton

Treatment of hereditary angioedema—single or multiple pathways to the rescue

A narrative review on sacubitril/valsartan and ventricular arrhythmias

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