Details

Autor(en) / Beteiligte

• Lee, Sunghye
• Kim, Yeomyeong
• Kim, Ye‐Seul
• Zhang, Haiying
• Noh, Minyoung
• Kwon, Young‐Guen

Titel

CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

Ist Teil von

• Allergy (Copenhagen), 2023-05, Vol.78 (5), p.1333-1346

Ort / Verlag

Denmark: Blackwell Publishing Ltd

Erscheinungsjahr

2023

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Background Over‐release of the vasoactive peptide bradykinin (BK) due to mutation in the SERPING1 gene is the leading cause of hereditary angioedema (HAE). BK directly activates endothelial cells and increases vascular permeability by disrupting the endothelial barrier, leading to angioedema affecting face, lips, extremities, gastrointestinal tract, and larynx. Although various pharmacological treatment options for HAE became available during the last decade, they are presently limited and pose a major economic burden on patients. To identify additional therapeutic options for HAE, we evaluated the effect of CU06‐1004, an endothelial dysfunction blocker, on BK‐induced vascular hyperpermeability and the HAE murine model. Methods To investigate the effect of CU06‐1004 on BK‐induced vascular hyperpermeability in vivo, we pre‐administrated WT mice with the drug and then induced vascular leakage through intravenous injection of BK and observed vascular alternation. Then, SERPING1 deficient mice were used for a HAE murine model. For an in vitro model, the HUVEC monolayer was pre‐treated with CU06‐1004 and then stimulated with BK. Results Bradykinin disrupted the endothelial barrier and formed interendothelial cell gaps, leading to hyperpermeability in vivo and in vitro. However, CU06‐1004 treatment protected the endothelial barrier by suppressing Src and myosin light chain activation via BK and alleviated hyperpermeability. Conclusion Our study shows that CU06‐1004 oral administration significantly reduced vascular hyperpermeability in the HAE murine model by protecting the endothelial barrier function against BK stimulation. Therefore, protecting endothelium against BK with CU06‐1004 could serve as a potential prophylactic/therapeutic approach for HAE patients. Increased vascular permeability due to BK is the leading cause of the C1‐INH‐HAE. CU06‐1004 oral administration significantly alleviated vascular hyperpermeability in C1‐INH‐HAE murine in vivo model by protecting vascular integrity. CU06‐1004 protected the endothelial barrier from BK‐induced interendothelial cell gap formation by inhibiting VE‐cadherin phosphorylation and stress fiber formation.Abbreviations: BK, bradykinin; C1‐INH, C1 esterase inhibitor; C1‐INH‐HAE, hereditary angioedema caused by C1 esterase inhibitor deficiency; CTRL, control; CU06‐1004, endothelial dysfunction blocker; EC, endothelial cell; F‐actin, filamentous actin; HMW kininogen, high‐molecular‐weight kininogen; KO, knock‐out; MLC, myosin light chain; Src, non‐receptor tyrosine kinase; VE‐cadherin, vascular endothelial cadherin; WT, wild type