Abstract
Background: Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflammatory diseases, including atherosclerosis, obesity and NAFLD, through to its anti-inflammatory effect. Methods: The present study investigates the influence of prolonged treatment with TUG-891-FFAR4 agonist on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. Results: TUG-891 administration has led to the reduction of atherosclerotic plaque size and necrotic cores in an apoE-knockout mice model. TUG-891-treated mice were administered subcutaneously at a dose of 20 mg/kg three times a week for 4 months. The FFAR4 agonist reduced the content of pro-inflammatory M1-like macrophages content in atherosclerotic plaques, as evidenced by immunohistochemical phenotyping and molecular methods. In atherosclerotic plaque, the population of smooth muscle cells increased as evidenced by α-SMA staining. We observed changes in G-CSF and eotaxin markers in the plasma of mice; changes in the levels of these markers in the blood may be related to macrophage differentiation. Importantly, we observed a significant increase in M2-like macrophage cells in atherosclerotic plaque and peritoneum. Conclusions: Prolonged administration of TUG-891 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR4 receptor holds promise for a new approach in the prevention or treatment of atherosclerosis.
Highlights
According to current paradigm, atherosclerosis is a systemic low-grade inflammatory disease characterized by progressive changes in arterial walls that involve many types of cells [1,2]
The major finding in this work is that inhibition of atherosclerosis by a selective FFAR4 agonist TUG-891 is associated with a significant shift in the polarization of macrophages in atherosclerotic plaques towards the M2 phenotype
Our data point to the role of FFAR4 in the modulation of macrophage phenotype and, in a more general context, highlight the importance of in-plaque balance between different macrophage phenotype species as an important modulator of atherogenesis
Summary
Atherosclerosis is a systemic low-grade inflammatory disease characterized by progressive changes in arterial walls that involve many types of cells [1,2]. Dysfunction of endothelial cells, phenotypic changes of vascular smooth muscle cells (VSMC), as well as inflammatory stimulation and infiltration of lymphocytes and monocytes into the vessel wall were all reported to contribute to atherogenesis and formation of atherosclerotic plaques [1,3]. Anti-atherosclerotic action of GW9508, a synthetic agonist of FFAR1 and FFAR4, was associated with a decrease of M1 macrophage content within the plaque [14] It was the first study with the administration of a synthetic agonist of the FFARs in a mouse model of atherosclerosis, its results are limited due to the non-selective action of GW9508 and its marked toxicity during prolonged administration [14]. We investigated whether the activation of FFAR4 by TUG-891 may inhibit formation of atherosclerotic lesions in apoE-knockout mice and elicit beneficial changes in plaque macrophage polarization
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