Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo
| Autor: | Sampson, Amanda K., Irvine, Jennifer C., Shihata, Waled A., Dragoljevic, Dragana, Lumsden, Natalie, Huet, Olivier, Barnes, Tyrone, Unger, Thomas, Steckelings, Ulrike M., Jennings, Garry L., Widdop, Robert E., Chin-Dusting, Jaye P. F. |
|---|---|
| Přispěvatelé: | Bedrijfsbureau CD, RS: CARIM School for Cardiovascular Diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Leukocytes/cytology Sulfonamides/chemistry Human Umbilical Vein Endothelial Cells/drug effects Thiophenes Receptor Angiotensin Type 2 Mice Apolipoproteins E Reactive Oxygen Species/metabolism Inflammation/drug therapy Signal Transduction/drug effects Cell Adhesion Human Umbilical Vein Endothelial Cells Leukocytes Thiophenes/chemistry Animals Humans Cell Adhesion/drug effects Cells Cultured Inflammation Mice Knockout Sulfonamides Apolipoproteins E/deficiency Receptor Angiotensin Type 2/agonists Themed Section: Research Papers Reactive Oxygen Species Signal Transduction |
| Zdroj: | Sampson, A K, Irvine, J C, Shihata, W A, Dragoljevic, D, Lumsden, N, Huet, O, Barnes, T, Unger, T, Steckelings, U M, Jennings, G L, Widdop, R E & Chin-Dusting, J P 2016, ' Compound 21, a selective agonist of angiotensin AT 2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo ', British Journal of Pharmacology, vol. 173, no. 4, pp. 729-740 . https://doi.org/10.1111/bph.13063 British Journal of Pharmacology, 173(4), 729-740. Wiley |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.13063 |
| Popis: | Background and PurposeAngiotensin AT(2) receptors are upregulated in disease states such as atherosclerosis and blockade of the AT(2) receptors exacerbates plaque formation. Direct stimulation of these receptors is anti-atherogenic but the mechanisms and pathways involved remain unknown. We examined the effect of direct AT(2) receptor stimulation with Compound 21 (C21) on the leukocyte adhesion cascade in vitro, right through to plaque formation in vivo. Experimental ApproachEffects of C21 on TNF-induced inflammation were assessed in human umbilical vein endothelial cells (HUVECs), activation of monocytes, polarisation of monocyte-derived macrophages and in intact mouse aortae. Key ResultsC21 attenuated TNF-induced: monocyte adhesion to cultured HUVECs, adhesion molecule expression and abolished TNF-induced ROS production. TNF-induced NFB translocation from the cytoplasm to the nucleus, essential for cytokine production, was prevented by C21. C21 did not influence monocyte activation or macrophage polarisation but did reduce TNF and IL-6 mRNA expression in M1 macrophages. The anti-inflammatory effects of C21 were abolished by an AT(2) receptor antagonist confirming that the effects of C21 were AT(2) receptor-mediated. Also, leukocyte adhesion and cytokine gene expression, induced by high-fat diet (HFD), was attenuated in ApoE(-/-) mice treated with C21. Plaque size and stability were improved with C21 treatment with increased smooth muscle cell composition and decreased lipid size, compared with HFD-saline treated mice. Conclusion and ImplicationsC21 prevented TNF-induced and HFD-induced vascular inflammation in vitro and in vivo. Our data provide strong evidence that the anti-atherosclerotic actions of C21 were due to vascular anti-inflammatory effects, mediated by AT(2) receptors. Linked ArticlesThis article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text