Department of Pediatrics at University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh, (R.M.C., D.M.C., A.B.-N., J.V.A., W.M.C.A., S.S., J.H., T.B.-N.), University of Pittsburgh, PA.
Center for Pediatrics Research in Obesity and Metabolism at UPMC Children's Hospital of Pittsburgh (R.M.C., A.B.-N., J.V.A., W.M.C.A., S.S., T.B.-N.), University of Pittsburgh, PA.
Hypertension. 2024 Apr;81(4):776-786. doi: 10.1161/HYPERTENSIONAHA.123.21888. Epub 2024 Jan 19.
Aldosterone has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of CCL5 (C-C motif chemokine ligand 5) and its receptor CCR5 (C-C motif chemokine receptor 5) are well known in infectious diseases, their contributions to aldosterone-induced vascular injury and hypertension remain unknown.
We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5) and CCR5 knockout (CCR5) mice treated with aldosterone (600 µg/kg per day for 14 days) while receiving 1% saline to drink. Vascular function was analyzed in aorta and mesenteric arteries, blood pressure was measured by telemetry and renal injury and inflammation were analyzed via histology and flow cytometry. Endothelial cells were used to study the molecular signaling whereby CCL5 induces endothelial dysfunction.
Aldosterone treatment resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression in CCR5 mice accompanied by endothelial dysfunction, hypertension, and renal inflammation and damage. CCR5 mice were protected from these aldosterone-induced effects. Mechanistically, we demonstrated that CCL5 increased NOX1 (NADPH oxidase 1) expression, reactive oxygen species formation, NFκB (nuclear factor kappa B) activation, and inflammation and reduced NO production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aorta incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking NOX1, NFκB, or CCR5.
Our data demonstrate that CCL5/CCR5, through activation of NFκB and NOX1, is critically involved in aldosterone-induced vascular and renal damage and hypertension placing CCL5 and CCR5 as potential therapeutic targets for conditions characterized by aldosterone excess.
醛固酮已被描述为通过引发加剧的无菌性血管炎症来引发心血管疾病。CCL5（C-C 基序趋化因子配体 5）及其受体 CCR5（C-C 基序趋化因子受体 5）的功能在传染病中众所周知，但其在醛固酮诱导的血管损伤和高血压中的作用尚不清楚。
我们分析了用醛固酮（每天 600μg/kg，持续 14 天）治疗并用 1%盐水饮用的野生型（CCR5）和 CCR5 敲除（CCR5）小鼠的血管特征、血压和肾脏损伤。在主动脉和肠系膜动脉中分析血管功能，通过遥测法测量血压，并通过组织学和流式细胞术分析肾脏损伤和炎症。使用内皮细胞研究 CCL5 诱导内皮功能障碍的分子信号。
醛固酮治疗导致 CCR5 小鼠的循环 CCL5 水平和血管 CCR5 表达增加，伴有内皮功能障碍、高血压和肾脏炎症和损伤。CCR5 小鼠免受这些醛固酮诱导的作用。从机制上讲，我们证明 CCL5 增加了 NOX1（NADPH 氧化酶 1）的表达、活性氧的形成、NFκB（核因子 kappa B）的激活以及炎症，并减少了分离的内皮细胞中 NO 的产生。这些作用被用 Maraviroc 拮抗 CCR5 所消除。最后，用 CCL5 孵育的主动脉显示出严重的内皮功能障碍，这可以通过阻断 NOX1、NFκB 或 CCR5 来预防。
我们的数据表明，CCL5/CCR5 通过激活 NFκB 和 NOX1，在醛固酮诱导的血管和肾脏损伤以及高血压中起着关键作用，这使得 CCL5 和 CCR5 成为醛固酮过多引起的疾病的潜在治疗靶点。
