Abstract
Background: Type 2 diabetes (T2DM) affects billions of patients and has a pathophysiologically important inflammatory component. Macrophage plasticity in diabetes is impaired, and remains in a persistent proinflammatory state; yet currently, the cause of the inflammatory state is unknown. Phenylacetylglutamine (PAGln) is an amino acid metabolism end product that rises in T2DM patients and is associated with incident major adverse cardiovascular events. However, the role of PAGln in the inflammatory component of T2DM remains unknown. Purpose: Here, we aim to identify blood-based systemic factors for pathologic inflammation status and risk of atherosclerosis as they are highly reproducible at low cost and search for effective and safe agents to attenuate diabetic inflammatory complications. Methods: In vivo, phenylacetylglutamine was dissolved in normal saline and injected in mice daily (ip). The levels of PAGln were analyzed by liquid chromatography-mass spectrometry. The effect of PAGln on atherosclerosis progression was analyzed by Ldlr-/- mice, followed by a Western diet feeding for 12 weeks. In vitro, primary mice bone marrow-derived macrophages (BMDMs) and haematopoietic stem cells (HSCs) were treated with phenylacetylglutamine (100 uM) for the indicated time. Results: In vivo, increased immune cells and inflammatory macrophages were detected in PAGln-treated mice blood, spleens, bone marrow, and arteries. In vitro, PAGln leads to macrophage M1 polarization. The result of bone marrow transplantation on Ldlr-/- mice further confirmed the effect of PAGln on the central immune system of mice. Besides, the negative effects of PAGln could be rescued by ß-blockers. Conclusion: Our study unravels a novel mechanism by which PAGln accelerates atherosclerosis progression and causes pathologic inflammation by activating the ß2-adrenergic receptor. The negative effect of PAGln could be rescued by carvedilol (ß blocker). Thus, our recognition of chronic inflammation in diabetes needs to be revised, and understanding these mechanisms can inform alternative treatment strategies and refine atherosclerosis repair therapies for diabetic patients.
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