The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

International Journal of Molecular Sciences

Maria Jelinic¹  LauraJ Parry¹  ChenHuei Leo¹  Minh Deo²  Kelly O’Sullivan³  RebeccaH. Ritchie⁴  Mandy Li⁴  ChengXue Qin⁴  Jesse Walsh⁵  SarahA Marshall⁶ 

[1] Diabetes Institute, Victoria 3004, Australia;Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia;;Department of Physiology, Anatomy &;Heart Failure Pharmacology, Baker Heart &School of BioSciences, The University of Melbourne, Victoria 3010, Australia;The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia;

关键词: diabetes;    compound 17b;    endothelial dysfunction;    fpr1/2;   

DOI  :  10.3390/ijms21041384

来源: DOAJ

【 摘 要 】

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 Ca²⁺ 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 CaCl₂ evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca²⁺ 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.

【 授权许可】

Unknown