دورية أكاديمية
The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice
| العنوان: | The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice |
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| المؤلفون: | Sarah A Marshall, Cheng Xue Qin, Maria Jelinic, Kelly O’Sullivan, Minh Deo, Jesse Walsh, Mandy Li, Laura J Parry, Rebecca H. Ritchie, Chen Huei Leo |
| المصدر: | International Journal of Molecular Sciences, Vol 21, Iss 4, p 1384 (2020) |
| بيانات النشر: | MDPI AG |
| سنة النشر: | 2020 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | diabetes, compound 17b, endothelial dysfunction, fpr1/2, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | 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 Ca 2+ 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 CaCl 2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca 2+ 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1422-0067 |
| العلاقة: | https://www.mdpi.com/1422-0067/21/4/1384Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/b0bfb8dae61343d5a1d0ab4262788bf8Test |
| DOI: | 10.3390/ijms21041384 |
| الإتاحة: | https://doi.org/10.3390/ijms21041384Test https://doaj.org/article/b0bfb8dae61343d5a1d0ab4262788bf8Test |
| رقم الانضمام: | edsbas.71EC5646 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14220067 |
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| DOI: | 10.3390/ijms21041384 |