Activation AMPK in Hypothalamic Paraventricular Nucleus Improves Renovascular Hypertension Through ERK1/2-NF-κB Pathway.

IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI:10.1007/s12012-024-09888-9
Li-Yan Fu, Yu Yang, Rui-Juan Li, Abdoulaye Issotina Zibrila, Hua Tian, Xiu-Yue Jia, Jin-An Qiao, Jin-Min Wu, Jie Qi, Xiao-Jing Yu, Yu-Ming Kang
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Abstract

Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 μg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.

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通过ERK1/2-NF-κB途径激活下丘脑室旁核中的AMPK改善肾血管性高血压
高血压是一种全球流行的疾病,但其发病机理在很大程度上仍不清楚。AMP激活蛋白激酶(AMPK)是细胞能量代谢的营养敏感信号,对高血压的发病有一定影响。此前,我们发现在高血压大鼠的下丘脑室旁核(PVN)中,AMPK 的磷酸化(p-)形式下调,血管紧张素 II 1 型受体(AT1-R)和 p-ERK1/2 上调。然而,高血压期间下丘脑室旁核 AMPK 与 AT1-R 之间关系的确切机制仍不清楚。因此,我们假设 AMPK 通过 ERK1/2-NF-κB 通路调节 PVN 中的 AT1-R,从而抑制交感神经活动并改善高血压。为了验证这一假设,我们采用了通过双肾单夹(2K1C)和假手术(SHAM)建立的新血管性高血压动物模型。将人工脑脊液(aCSF)(用作载体)或 5-氨基-1-β-D-呋喃核糖基咪唑-4-甲酰胺(AICAR,一种 AMPK 激活剂,60 μg/天)微量注射到这些大鼠的 PVN 中,持续 4 周。在 2K1C 大鼠中,收缩压(SBP)和循环去甲肾上腺素(NE)均有所增加。此外,与 SHAM 大鼠相比,高血压大鼠 PVN 中 p-AMPK 和 p-AMPK/AMPK 表达降低,p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 表达升高,NF-κB p65 活性增加。给 2K1C 大鼠双侧 PVN 注射 AMPK 激活剂 AICAR 四周后,NE 水平和 SBP 均有所降低,p-AMPK 和 p-AMPK/AMPK 的表达增加,NF-κB p65 活性降低,p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 的表达减少。这项研究的数据表明,激活 PVN 中的 AMPK 可通过抑制 ERK1/2-NF-κB 通路抑制 AT1-R 的表达,降低交感神经系统的活性,从而改善高血压。
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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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