Nogo-RhoA/ROCK信号通路在高血压心肌肥厚中的调控机制研究

Cardiac hypertrophy is an important risk factor for cardiovascular event and mortality in patients with hypertension.Retardating cardiac hypertrophy has been known to be a key way to reduce cardiovascular events and mortality. Our preliminary results showed cardiac norepinephrine content increase and cardiac sympathetic nerve innervation decrease were associated with cardiac hypertrophy. Therefore, cardiac NE content and sympathetic nerve remodeling are regarded as targets to regulating hypertensive cardiac hypertrophy in our study. Norepinephrine transporter (NET) in presynaptic membrane of sympathetic nerve, which can regulate cardiac norepinephrine (NE) content, has been considered as a key molecular to retard cardiac hypertrophy, and NET reuptaking NE ability is regulated by ROCK. We hypothesize that Nogo-Rho/ROCK signaling pathway is involved in regulating NET reuptaking ability and sympathetic nerve remodeling, and thereafter regulating cardiac hypertrophy development. To demonstrate the hypothesis, we have have successfully prepared spontaneously hypertensive rats with hypertensive cardiac hypertrophy and myocardial cell model cultured with sympathetic nerve innervation, and we revealed that Nogo A was ighly expressed in cardiac musle of hypertensive patients. We will further demonstrated Nogo-RhoA/ROCK-NET-NE- sympathetic nerve remodeling signial pathway is involved in regulating cardiac hypertrophy, and highlight multiple targets to intervene cardiac hypertrophy in hypertensive patients.

心肌肥厚是高血压患者发生心血管事件和死亡的重要危险因素，干预心肌肥厚是降低心血管事件和死亡的关键环节。我们前期研究提示心肌去甲肾上腺素（NE）含量增加与心脏交感神经分布密度减低与高血压心肌肥厚密切相关。于是我们将调控心肌NE含量与心脏交感神经重塑作为干预高血压心肌肥厚的靶标。已知心脏交感神经突触前膜上去甲肾上腺素转运蛋白（NET）是控制心肌NE含量的重要因子，NET再摄取功能受ROCK的调节。我们推测Nogo-Rho/ROCK信号通路或可通过影响NET再摄取功能与心脏交感神经重塑调控高血压心肌肥厚。为验证这一假说，本项目组已成功建立高血压心肌肥厚动物模型和交感神经支配的心肌细胞模型，并且在高血压心肌肥厚患者心肌标本中检测出Nogo A高表达。我们拟进一步证明高血压心肌肥厚进程中存在Nogo-RhoA/ROCK-NET-NE-交感神经重塑调节轴，从为临床多靶点干预高血压心肌肥厚提供新思路。

心肌肥厚是高血压患者发生心血管事件和死亡的重要危险因素，干预心肌肥厚是降低心血管事件和死亡的关键环节。心肌去甲肾上腺素（NE）含量增加与心脏交感神经分布密度减低与高血压心肌肥厚密切相关。于是我们将调控心肌NE含量与心脏交感神经重塑作为干预高血压心肌肥厚的靶标。已知心脏交感神经突触前膜上去甲肾上腺素转运蛋白（NET）是控制心肌NE含量的重要因子，NET再摄取功能受ROCK的调节。.本项目研究了心脏交感神经重塑与NET表达与再摄取功能在高血压心肌肥厚中的作用；Nogo/NgR-RhoA/ROCK 信号通路对心脏交感神经重塑与NET 再摄取功能的调节作用；Nogo/NgR-RhoA/ROCK 信号通路是否介导调节心脏交感神经重塑与NET 再摄取功能影响高血压心肌肥厚。研究结果显示，交感神经切除术可降低交感神经活性，对心肌重构有影响。6-OHDA造成的化学性去交感神经亦可抑制高血压导致的心肌肥厚和心肌纤维化。无论心脏交感神经切除术，还是化学去心脏交感神经均可抑制高血压导致的心肌肥厚和心肌纤维化。抑制Nogo促进自发性高血压大鼠心肌肥厚和纤维化的发生；阻断ROCK对心肌肥厚和心肌纤维化有抑制作用；NET是ROCK的下游作用分子；Nogo /ROCK-NET信号通路参与自发性高血压大鼠心肌肥厚和纤维化的调节。此外，我们的研究显示，死亡危险增加与交感神经兴奋性指标——心率增加密切相关，心率≤60bpm与窦性节律HFpEF患者预后改善密切相关。β受体阻滞剂使用与死亡率降低有关，较低心率与窦性节律HFpEF患者死亡率降低相关。我们的研究为临床多靶点干预高血压心肌肥厚提供了新思路。