基于microRNA差异表达的补肾降压方对自发性高血压大鼠左室肥厚影响的分子机制

Hypertension is one of the most important risk factors of chronic non-communicable diseases such as stroke, myocardial infarction, heart failure and so on. It seriously affects the structure and function of heart, brain, kidney and other vital organs. Left ventricular hypertrophy (LVH) is the significant and independent cardiovascular risk factor induced by elevated blood pressure. Therefore, reversing LVH has become an important target for the management of hypertension. Recent studies have shown the potential role of microRNA in the pathological process of cardiovascular diseases and pathological LVH. It is one of the most important regulating factors for hypertension and its related ventricular hypertrophy. Previous researches have shown that, bushen jiangya decoction (BJD), a Chinese herbal medicine based on the therapeutic principle of tonifying kidney, could lower blood pressure smoothly and reverse LVH. The mechanism maybe related to up-regulating microRNA-1 to inhibit the expression of ERK signaling pathway and its key targets. So it is supposed that BJD could reverse LVH by regulating microRNA network. We aimed to investigate the molecular mechanisms of BJD on reversing LVH from the perspective of differences in gene expression between microRNA and its key targets by establishing the typical models of spontaneously hypertensive rats (SHR) with LVH and neonatal rat cardiac myocyte hypertrophy induced by angiotensin II. The study can provide the scientific basis for treatment of hypertension based on the therapeutic principle of tonifying kidney. It also offers the new ideas to find new treatments and new drug targets for treatment of hypertension.

高血压严重影响心脑肾等重要脏器的结构和功能，左室肥厚（LVH）是高血压导致的重要靶器官损害，是心血管病发生的独立危险因素，逆转LVH已成为治疗高血压病的重要目标。最新研究表明，microRNA不仅是高血压病最重要的调控因子之一，而且与心室肥厚发病机制密切相关。我们的前期研究显示，基于补肾治法的补肾降压方能稳定血压、逆转LVH，其作用机制与上调microRNA-1水平进而抑制ERK信号通路及其关键靶基因过表达有关。因此，我们推测补肾降压方可能是通过调控microRNA网络而达到逆转LVH作用。本课题通过建立自发性高血压大鼠心室肥厚及血管紧张素II诱导乳鼠心肌细胞肥大模型，我们拟从microRNA及其靶基因差异表达上揭示补肾降压方对自发性高血压大鼠左室肥厚的分子机制。该研究可为补肾法治疗高血压病提供科学依据，也可为临床上寻找治疗高血压病新的治疗方法和新的药物靶点提供新思路。

高血压严重影响心脑肾等重要脏器的结构和功能，左室肥厚（LVH）是高血压导致的重要靶器官损害，是心血管病发生的独立危险因素，逆转LVH已成为治疗高血压病的重要目标。最新研究表明，microRNA不仅是高血压病最重要的调控因子之一，而且与心室肥厚发病机制密切相关。我们的前期研究显示，基于补肾治法的补肾降压方能稳定血压、逆转LVH，其作用机制与上调microRNA-1水平进而抑制ERK信号通路及其关键靶基因过表达有关。因此，我们推测补肾降压方可能是通过调控microRNA网络而达到逆转LVH作用。本课题通过建立自发性高血压大鼠心室肥厚及血管紧张素II诱导乳鼠心肌细胞肥大模型，我们拟从microRNA及其靶基因差异表达上揭示补肾降压方对自发性高血压大鼠左室肥厚的分子机制。研究发现：（1）补肾降压方能够在SHR模型上稳定血压，减慢心率；（2）补肾降压方能在一定程度上逆转心室肥厚；（3）补肾降压方能够调节心室肥厚的microRNA表达；（4）补肾降压方能够下调rno-miR-872-5p，上调rno-miR-298-5p；（5）预测研究发现rno-miR-872-5p有108个靶基因，rno-miR-298-5p有399个靶基因；（6）体内外验证研究发现，rno-miR-872-5p及其靶基因Smad1之间存在负性调控关系；rno-miR-298-5p及其靶基因Rassf4之间存在正性调控关系；（7）补肾降压方逆转高血压心室肥厚的作用机制可能与调节microRNA及其关键靶基因有关。该研究可为补肾法治疗高血压病提供科学依据，也可为临床上寻找治疗高血压病新的治疗方法和新的药物靶点提供新思路。