目标:牙龈卟啉单胞菌(P.牙龈),一种主要的牙周病原体,与动脉粥样硬化的进展和恶化有关。在这项研究中,我们的目的是研究胃泌素释放肽受体拮抗剂,RC-3095可以减弱牙龈卟啉单胞菌LPS诱导的内皮细胞和巨噬细胞的炎症反应,以及用牙龈卟啉单胞菌LPS处理的ApoE-/-小鼠模型中的动脉粥样硬化。
方法:使用HUVECs和大鼠主动脉内皮检查RC-3095对牙龈卟啉单胞菌LPS诱导的内皮炎症的影响。通过暴露于牙龈卟啉单胞菌LPS,将THP-1细胞极化为M1巨噬细胞,有或没有RC-3095。通过注射牙龈卟啉单胞菌LPS,在高脂喂养的雄性ApoE-/-小鼠中评估RC-3095对动脉粥样硬化进展的影响,RC-3095,或两者的组合。
结果:RC-3095通过抑制NF-κB依赖性的ICAM-1和VCAM-1的表达,显著降低牙龈卟啉单胞菌LPS诱导的白细胞与内皮细胞和主动脉内皮的粘附。此外,RC-3095通过阻断MAPK和NF-κB信号通路抑制牙龈卟啉单胞菌LPS诱导的M1巨噬细胞极化。此外,RC-3095减少ApoE-/-小鼠动脉粥样硬化病变面积,通过牙龈卟啉单胞菌LPS注射加速,降低动脉粥样硬化小鼠主动脉组织中ICAM-1和VCAM-1的表达。
结论:RC-3095可以减轻牙龈卟啉单胞菌LPS诱导的内皮细胞炎症,巨噬细胞极化,和动脉粥样硬化进展,提示其作为牙周病原体相关动脉粥样硬化的治疗方法的潜力。
OBJECTIVE: Porphyromonas gingivalis (P. gingivalis), one of the major periodontopathogens, is associated with the progression and exacerbation of atherosclerosis. In this study, we aimed to investigate whether the gastrin-releasing peptide receptor antagonist, RC-3095, could attenuate P. gingivalis LPS-induced inflammatory responses in endothelial cells and macrophages, as well as atherosclerosis in an ApoE-/- mouse model treated with P. gingivalis LPS.
METHODS: The effect of RC-3095 on P. gingivalis LPS-induced endothelial inflammation was examined using HUVECs and rat aortic endothelium. THP-1 cells were polarized into M1 macrophages by exposure to P. gingivalis LPS, with or without RC-3095. The effect of RC-3095 on atherosclerosis progression was assessed in high-fat-fed male ApoE-/- mice through injections of P. gingivalis LPS, RC-3095, or a combination of both.
RESULTS: RC-3095 significantly reduced P. gingivalis LPS-induced leukocyte adhesion to endothelial cells and aortic endothelium by suppressing NF-κB-dependent expressions of ICAM-1 and VCAM-1. In addition, RC-3095 inhibited the P. gingivalis LPS-induced polarization of M1 macrophages by blocking the MAPK and NF-κB signaling pathways. Moreover, RC-3095 decreased the area of atherosclerotic lesions in ApoE-/- mice, which was accelerated by P. gingivalis LPS injection, and lowered the expressions of ICAM-1 and VCAM-1 in the aortic tissue of mice with atherosclerosis.
CONCLUSIONS: RC-3095 can alleviate P. gingivalis LPS-induced endothelial inflammation, macrophage polarization, and atherosclerosis progression, suggesting its potential as a therapeutic approach for periodontal pathogen-associated atherosclerosis.