Takesue Ko, Kishi Takuya, Hirooka Yoshitaka, Sunagawa Kenji
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Department of Collaborative Research Institute of Innovation for Cardiovascular Diseases, Kyushu University Center for Disruptive Cardiovascular Medicine, Fukuoka, Japan.
J Cardiol. 2017 Jan;69(1):84-88. doi: 10.1016/j.jjcc.2016.01.004. Epub 2016 Feb 10.
Inflammation within paraventricular nucleus of the hypothalamus (PVN), a key circulatory control center in the hypothalamus, is an important pathology of sympathetic hyperactivity. Brain inflammation is mainly mediated by microglia, innate immune cells in the brain. Activated microglia produce inflammatory cytokines with alteration of their morphology. Increase in inflammatory cytokines synthesis coincides with activation of microglia within PVN of angiotensin II-induced hypertensive model and myocardial infarction-induced heart failure model. Although the increase in inflammatory cytokines and the microglial activation within PVN were also seen in spontaneously hypertensive rats (SHR), the model of essential hypertension, their involvement in blood pressure regulation has still be fully clarified. In the present study, we examined whether activated microglia within PVN were involved in maintenance of established severe hypertension with sympathoexcitation.
Minocycline (25mg/kg/day), an inhibitor of microglial activation, or vehicle were orally administered to stroke-prone SHR (SHRSP) and normotensive Wistar-Kyoto (WKY) rats for 2 weeks from 15-weeks-old, the age of established hypertension.
Systolic blood pressure was comparable between minocycline treated-SHRSP and vehicle treated-SHRSP, whereas morphological analysis of microglia revealed smaller cell size in minocycline treated-SHRSP than vehicle treated-SHRSP, implying that minocycline deactivated microglia within PVN.
Activated microglia with morphological alteration within PVN are not involved in the maintenance of established severe hypertension, and inflammation within PVN could not be the therapeutic target of established hypertension.
下丘脑室旁核（PVN）是下丘脑关键的循环控制中心，该部位的炎症是交感神经过度活跃的重要病理表现。脑内炎症主要由小胶质细胞介导，小胶质细胞是脑内的固有免疫细胞。活化的小胶质细胞会产生炎症细胞因子，其形态也会发生改变。在血管紧张素II诱导的高血压模型和心肌梗死诱导的心力衰竭模型中，炎症细胞因子合成的增加与PVN内小胶质细胞的活化同时出现。尽管在原发性高血压模型自发性高血压大鼠（SHR）中也观察到了PVN内炎症细胞因子的增加和小胶质细胞的活化，但它们在血压调节中的作用仍有待充分阐明。在本研究中，我们检测了PVN内活化的小胶质细胞是否参与了已确立的伴有交感神经兴奋的重度高血压的维持。
从15周龄（即高血压确立的年龄）开始，对易卒中型SHR（SHRSP）和正常血压的Wistar-Kyoto（WKY）大鼠口服给予小胶质细胞活化抑制剂米诺环素（25mg/kg/天）或赋形剂，持续2周。
米诺环素处理的SHRSP和赋形剂处理的SHRSP之间的收缩压相当，而小胶质细胞的形态学分析显示，米诺环素处理的SHRSP中小胶质细胞的细胞大小比赋形剂处理的SHRSP小，这意味着米诺环素使PVN内的小胶质细胞失活。
PVN内形态改变的活化小胶质细胞不参与已确立的重度高血压的维持过程，PVN内的炎症不能成为已确立高血压的治疗靶点。
