Aims

Hypertension is one of the leading causes of cardiovascular mortality and morbidity. It is associated with severe cardiac and vascular dysfunction. Double-stranded RNA-dependent protein kinase (PKR), is a known inducer of inflammation and apoptosis. However, no research has been done to elucidate the role of the PKR in an experimental model of hypertension, and related cardiovascular complications.

Main methods

L-NAME (N^G-Nitro-L-arginine-methyl ester) was used to induce the hypertension. Imoxin treatment was given to Wistar rats for the four weeks along with the L-NAME, to investigate the influence on the hypertension. Changes in physiological parameter were assessed by recording non-invasive blood pressure. Expression of PKR and downstream markers for inflammation, fibrosis, and vascular damage in rat heart and aorta was determined by western blot and immunohistochemistry. Histological examination and fibrosis assessment were done by using assay kits. Vascular reactivity was determined by ex-vivo isometric tension studies on rat aortic rings.

Key findings

L-NAME-treated rats showed a significant increase in PKR expression followed by cardiac damage and vascular alterations compared to that of control animals. Results of western blot and immunohistochemistry indicate a significant increase in the inflammatory markers downstream to PKR. Endothelium-dependent vascular relaxation was significantly impaired in L-NAME administered rats. All effects of the L-NAME were attenuated by selective inhibition of PKR by imoxin.

Significance

Alterations in the heart and vasculature could be mediated in part by activation of the PKR pathway. Hence selective inhibition of PKR has therapeutic potential for combating hypertension and associated cardiovascular complications.

中文翻译：

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PKR抑制剂imoxin可预防L-NAME治疗的大鼠的高血压，内皮功能障碍以及心脏和血管重构。

目的

高血压是心血管疾病死亡率和发病率的主要原因之一。它与严重的心脏和血管功能障碍有关。双链RNA依赖性蛋白激酶（PKR），是炎症和凋亡的已知诱导剂。但是，尚未进行任何研究来阐明PKR在高血压和相关心血管并发症的实验模型中的作用。

主要方法

L-NAME（N ^{G ^} -硝基-L-精氨酸甲基酯）用于诱导高血压。对Wistar大鼠和L-NAME进行为期4周的Imoxin处理，以研究其对高血压的影响。通过记录非侵入性血压来评估生理参数的变化。通过western印迹和免疫组织化学确定大鼠心脏和主动脉中PKR的表达以及炎症，纤维化和血管损伤的下游标记。使用化验试剂盒进行组织学检查和纤维化评估。血管反应性是通过对大鼠主动脉环的离体等距张力研究确定的。

主要发现

与对照动物相比，用L-NAME治疗的大鼠的PKR表达显着增加，随后出现心脏损害和血管改变。免疫印迹和免疫组织化学结果表明，PKR下游的炎症标记显着增加。给予L-NAME的大鼠的内皮依赖性血管舒张作用显着受损。L-NAME的所有作用均被imoxin选择性抑制PKR所减弱。

意义

心脏和脉管系统的改变可能部分由PKR途径的激活介导。因此，选择性抑制PKR具有抗高血压和相关心血管并发症的治疗潜力。