Inhibition of CB1R in the Hypothalamic Paraventricular Nucleus Ameliorates Hypertension Through Wnt/β-Catenin/RAS Pathway.

IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2024-10-28 DOI:10.1007/s12012-024-09938-2
Hong-Li Gao, Yu Yang, Hua Tian, Li-Yan Fu, Kai-Li Liu, Xiu-Yue Jia, Xiao-Lian Shi, Yu-Ming Kang, Xiao-Jing Yu
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Abstract

The hypothalamic paraventricular nucleus (PVN), as an important integrating center, plays a prominent role in the pathogenesis of hypertension, in maintaining the stability of cardiovascular activity through peripheral sympathetic nervous activity and secretion of various humoral factors. Acknowledging that the mechanistic targets of the endocannabinoid type 1 receptor (CB1R) are the key signaling systems involved in the regulation of hypertension, we sought to clarify whether inhibition of CB1R within the PVN ameliorates hypertension through Wnt/β-catenin/RAS pathway. Spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats were randomly assigned to different groups and treated with bilateral PVN injections of AM251 (CB1R antagonist, 10 µg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for four weeks. Bilateral PVN injections of AM251 significantly decreased the heart rate, the body weight and the mean arterial pressure in SHRs. AM251 lowered the expression of CB1R, Wnt3, active-β-catenin, p-IKKβ, RAS components, pro-inflammatory cytokines and elevated the expression level of Glycogen synthase kinase3β and Superoxide Dismutase in the PVN of hypertensive rats. Our findings suggest that inhibition of CB1R in the PVN ameliorates hypertension through Wnt/β-catenin/RAS pathway and broaden our current understanding of the pathological mechanism and clinical treatment of hypertension.

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抑制下丘脑室旁核中的 CB1R 可通过 Wnt/β-Catenin/RAS 通路改善高血压状况
下丘脑室旁核(PVN)作为一个重要的整合中枢,通过外周交感神经活动和分泌各种体液因子维持心血管活动的稳定,在高血压的发病机制中发挥着突出的作用。鉴于内源性大麻素1型受体(CB1R)的机理靶点是参与调控高血压的关键信号系统,我们试图阐明抑制PVN内的CB1R是否能通过Wnt/β-catenin/RAS途径改善高血压。将自发性高血压大鼠(SHRs)和Wistar Kyoto大鼠随机分配到不同的组,双侧PVN注射AM251(CB1R拮抗剂,10 µg/h)或药物(人工脑脊液,aCSF)治疗四周。双侧皮质神经网注射 AM251 能显著降低 SHR 的心率、体重和平均动脉压。AM251 降低了高血压大鼠 PVN 中 CB1R、Wnt3、活性-β-catenin、p-IKKβ、RAS 成分、促炎细胞因子的表达,并提高了糖原合酶激酶 3β 和超氧化物歧化酶的表达水平。我们的研究结果表明,通过 Wnt/β-catenin/RAS 通路抑制 PVN 中的 CB1R 可改善高血压,这拓宽了我们目前对高血压病理机制和临床治疗的认识。
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来源期刊
Cardiovascular Toxicology
Cardiovascular Toxicology 医学-毒理学
CiteScore
6.60
自引率
3.10%
发文量
61
审稿时长
>12 weeks
期刊介绍: Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.
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