Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension.

IF 16.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-09-13 Epub Date: 2024-08-23 DOI:10.1161/CIRCRESAHA.124.324722

Qingqing Chu, Yujia Li, Jichao Wu, Yanjiao Gao, Xiangyun Guo, Jing Li, Hang Lv, Min Liu, Wei Tang, Peng Zhan, Tao Zhang, Huili Hu, Hong Liu, Jinpeng Sun, Xiaojie Wang, Fan Yi

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Abstract

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.

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通过 GPR183 感知氧杂环醇引发高血压的内皮衰老

背景：尽管内皮功能障碍是高血压和相关心血管/肾损伤发生的第一步，但目前仍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G蛋白偶联受体，用于氧化甾醇和胆固醇的羟化代谢产物，在脂质代谢和免疫反应中具有多方面的作用。然而，GPR183 在调节内皮功能方面的作用仍然未知：方法：通过建立两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（Ang II）诱导的高血压小鼠，产生了内皮特异性 GPR183 基因敲除小鼠，用于研究 GPR183 在内皮衰老中的作用。该研究进行了超声心动图、透射电子显微镜、血压测量、血管舒张反应实验、流式细胞仪分析和染色质免疫沉淀分析：结果：高血压小鼠的内皮细胞 GPR183 被显著诱导，这在高血压肾病患者的肾活检中得到了进一步证实。内皮特异性 GPR183 的缺乏明显减轻了高血压小鼠的心血管和肾脏损伤。此外，我们还发现 GPR183 可调节高血压小鼠和老龄小鼠的内皮衰老。从机制上讲，GPR183 通过抑制 PER1（周期 1）的表达破坏了昼夜节律信号传导，从而通过 cAMP/PKA（蛋白激酶 A）/CREB（cAMP-反应元件结合蛋白）信号传导途径促进了内皮衰老和功能障碍。重要的是，NIBR189或克霉唑对氧杂环醇-GPR183轴的药理抑制可改善高血压小鼠的内皮衰老和心血管/肾损伤：本研究发现了 GPR183 在促进内皮衰老中的作用，而这一作用此前尚未被认识。以 GPR183 为药理靶点可能是治疗高血压及其相关并发症的一种创新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.