Abstract
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.
Highlights
The formyl peptide receptor (FPR) family belongs to a group of G-protein coupled receptors that play key roles in the regulation and resolution of inflammation
There are three FPRs identified in humans (FPR1, FPR2, and FPR3) [1] all responding to a wide variety of peptide and small-molecule-based agonist and antagonists [2]
We demonstrated that vascular relaxation to Compound 17b (Cmpd17b) was still maintained after inhibition of nitric oxide (NO) and the sGC signalling pathway, indicating that Cmpd17b is not dependent on the NO pathway
Summary
The formyl peptide receptor (FPR) family belongs to a group of G-protein coupled receptors that play key roles in the regulation and resolution of inflammation. There are three FPRs identified in humans (FPR1, FPR2, and FPR3) [1] all responding to a wide variety of peptide and small-molecule-based agonist and antagonists [2]. FPR1 and FPR2 are expressed in a variety of tissues and cell types, but predominantly in inflammatory cells, such as neutrophils and monocytes [3]. The role of FPR3 is less clear with expression evident on dendritic cells [1,3]. Evidence for an important role of FPRs in promoting anti-inflammatory processes in the cardiovascular system has been well documented. Activation of FPR2 caused the phagocytosis of apoptotic neutrophils [7], inhibited neutrophil-platelet aggregation [8], reduced leukocyte adhesion to endothelial cells [9], and attenuated tumour necrosis factor-α-induced oxidative stress and cell adhesion markers in human dermal microvascular endothelial cells [10]
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