Dai Hai-Long, Hu Wei-Yuan, Jiang Li-Hong, Li Le, Gaung Xue-Feng, Xiao Zhi-Cheng
Department of Cardiology, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China.
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Sci Rep. 2016 Jun 10;6:27600. doi: 10.1038/srep27600.
The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38(KI/+)) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38(KI/+) hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction.
高血压相关认知障碍的发病机制尚未得到充分阐明，需要新的分子靶点。p38丝裂原活化蛋白激酶（MAPK）通路在高血压靶器官损伤中起重要作用。在阿尔茨海默病（AD）脑组织中可见活化的p38 MAPK。在本研究中，我们发现血管紧张素II依赖性高血压C57BL/6小鼠海马CA1区的长时程增强（LTP）降低，CA1锥体细胞上树突棘的密度减少，海马中磷酸化p38蛋白表达升高，且认知功能受损。在体内，使用p38杂合子敲低小鼠（p38(KI/+)）模型，我们发现敲低血管紧张素II依赖性p38(KI/+)高血压小鼠海马中的p38 MAPK可导致认知功能和海马突触可塑性的改善。在体外，用p38 MAPK抑制剂SKF86002处理C57BL/6高血压小鼠的海马脑片可改善LTP。我们的数据表明，p38 MAPK可能是高血压相关认知功能障碍的一个潜在治疗靶点。
