Şeren Nazlıcan, Dovinova Ima, Birim Derviş, Kaftan Gizem, Barancik Miroslav, Erdogan Mumin Alper, Armagan Güliz
Master Program in Biochemistry, Graduate School of Health Sciences, Ege University, 35100, Bornova, Izmir, Turkey.
Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Dubravska Cesta 9, 84104, Bratislava, Slovakia.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan;397(1):411-421. doi: 10.1007/s00210-023-02619-x. Epub 2023 Jul 17.
The decrease in tight junction proteins and their adapter proteins in the hypertensive brain is remarkable. Here, we aimed to investigate tight junction proteins and peroxisome proliferator-activated receptor (PPARγ) activation as well as inflammation factors and cell death proteins in the brainstem of hypertension models, namely spontaneously hypertensive rats (SHR) and borderline hypertensive rats (BHR). At first, SHR and BHR groups were treated with PPARγ agonist, pioglitazone. Then, occludin, claudin-1, claudin-2, claudin-12, ZO-1, and NF-κB p65 gene expression levels; pIKKβ, NF-κB p65, TNF, IL-1β, caspase-3, caspase-9 levels, and PARP-1 cleavage were evaluated. Significantly lower pIKKβ, NF-κB p65, TNF, and IL-1β levels were measured in pioglitazone-treated SHR. Results from this study confirm higher occludin (1.35-fold), claudin-2 (7.45-fold), claudin-12 (1.12-fold), and NF-κB p65 subunit (4.76-fold) expressions in the BHR group when compared to the SHR group. Pioglitazone was found effective in terms of regulating gene expression in SHR. Pioglitazone significantly increased occludin (8.17-fold), claudin-2 (2.41-fold), and claudin-12 (1.85-fold) mRNA levels, which were accompanied by decreased cleaved caspase-3, caspase-9 levels, PARP-1 activation, and proinflammatory factor levels in SHR (p ˂ 0.05). Our work has led us to conclude that alterations in tight junction proteins, particularly occludin, and cell death parameters in the brainstem following PPARγ activation may contribute to neuroprotection in essential hypertension.
高血压大鼠脑内紧密连接蛋白及其衔接蛋白的减少十分显著。在此，我们旨在研究高血压模型，即自发性高血压大鼠（SHR）和临界高血压大鼠（BHR）脑干中的紧密连接蛋白、过氧化物酶体增殖物激活受体（PPARγ）激活情况以及炎症因子和细胞死亡蛋白。首先，对SHR和BHR组给予PPARγ激动剂吡格列酮进行治疗。然后，评估闭合蛋白、紧密连接蛋白-1、紧密连接蛋白-2、紧密连接蛋白-12、闭锁小带蛋白-1（ZO-1）和核因子κB p65（NF-κB p65）的基因表达水平；磷酸化IκB激酶β（pIKKβ）、NF-κB p65、肿瘤坏死因子（TNF）、白细胞介素-1β（IL-1β）、半胱天冬酶-3、半胱天冬酶-9水平以及聚（ADP-核糖）聚合酶-1（PARP-1）的裂解情况。在吡格列酮治疗的SHR中，pIKKβ、NF-κB p65、TNF和IL-1β水平显著降低。本研究结果证实，与SHR组相比，BHR组中闭合蛋白（1.35倍）、紧密连接蛋白-2（7.45倍）、紧密连接蛋白-12（1.12倍）和NF-κB p65亚基（4.76倍）的表达更高。发现吡格列酮在调节SHR的基因表达方面有效。吡格列酮显著提高了闭合蛋白（8.17倍）、紧密连接蛋白-2（2.41倍）和紧密连接蛋白-12（1.85倍）的mRNA水平，同时SHR中的裂解半胱天冬酶-3、半胱天冬酶-9水平、PARP-1激活以及促炎因子水平降低（p＜0.05）。我们的研究得出结论，PPARγ激活后脑干中紧密连接蛋白，尤其是闭合蛋白的改变以及细胞死亡参数可能有助于原发性高血压中的神经保护作用。
