BACKGROUND Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period circadian regulator 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.

中文翻译：

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通过 GPR183 的氧甾醇感应触发高血压中的内皮衰老。


背景尽管内皮功能障碍是高血压和相关心血管/肾损伤发展的第一步，但仍然缺乏预防内皮功能障碍的有效治疗策略。 GPR183（G 蛋白偶联受体 183）是最近发现的一种氧化甾醇和胆固醇羟基化代谢物的 G 蛋白偶联受体，在脂质代谢和免疫反应中具有多效性作用。然而，GPR183在内皮功能调节中的作用仍不清楚。方法 生成内皮特异性 GPR183 敲除小鼠，并通过建立 2 个独立的高血压模型：醋酸去氧皮质酮/盐诱导的高血压小鼠和血管紧张素 II（血管紧张素 II）诱导的高血压小鼠，用于研究 GPR183 在内皮衰老中的作用。本研究进行了超声心动图、透射电镜、血压测量、血管舒张反应实验、流式细胞术分析和染色质免疫沉淀分析。结果 高血压小鼠体内内皮 GPR183 被显着诱导，这在高血压肾病受试者的肾活检中得到了进一步证实。 GPR183 的内皮特异性缺陷显着减轻了高血压小鼠的心血管和肾脏损伤。此外，我们发现 GPR183 调节高血压小鼠和老年小鼠的内皮衰老。从机制上讲，GPR183通过抑制PER1（周期昼夜节律调节因子1）表达来破坏昼夜节律信号传导，从而通过cAMP（环磷酸腺苷）/PKA（蛋白激酶A）/CREB（cAMP反应元件结合蛋白）信号通路促进内皮衰老和功能障碍。 重要的是，NIBR189 或克霉唑对氧固醇-GPR183 轴的药理学抑制可改善高血压小鼠的内皮衰老和心血管/肾脏损伤。结论 这项研究发现了 GPR183 在促进内皮衰老方面以前未被认识到的作用。 GPR183 的药理学靶向可能是高血压及其相关并发症的创新治疗策略。