肺动脉去神经术抑制肺动脉高压患者肺动脉与右心室重构的机制及转化研究

Pulmonary arterial hypertension (PH) is an incurable disease, featured by gressively increased pulmonary arterial pressure and pulmonary vessel resistance, leading to premature death induced by right ventricular failure. Overactivation of pulmonary arterial sympathetic nerves results in abnormal metabolism of energy, which activates G-protein coupling receptor kinase 2 (Grk2) with subsequent β-adrenergic receptor (β-AR) downregulation and dissentilization, inhibition of liver kinase B 1(LKB1), and right ventricular failure. However, the role of Grk2 and LKB1 in the progression of pulmonary arterial remodeling remains understudied. Pulmonary artery denervation (PADN), a novel technique innovated by our team, is reported to improve hemodynamic, to inhibit cellular synthesis and proliferation and subsequently to inhibit pulmonary artery remodeling, with resultant improvement of right ventricular function in patients with different etiologies of PH via activation of eNOS, inhibition of Akt-mTOR and p38/JNK signal pathways. Unfortunately, there are several key issues to be studied: wide discrimination in distribution of pulmonary arterial sympathetic nerves, 1st generation PADN catheter with distal circular ring not suitable for patients with severe enlarged pulmonary artery, and a lack of predicting system for ventricular function before and after PADN procedure. We found that Grk2 connected with LKB1 by co-IP technique in smooth muscle cells of pulmonary artery, PADN treatment significantly improve right ventricular longitudinal strain. Accordingly, our hypothesis is that PADN deserves its cardio-pulmonary protective effects by modulating PKA-Grk2-LKB1 signal pathway. In order to speed the translational research about PADN, the present study aims to achieve precise mapping of pulmonary arterial sympathetics and modify PADN, to analyse the safety and efficacy of PADN procedure, to create a comprehensive predictive and stratifying system based on echocardiography-derived parameters, and to identify the mechanisms correlated with PADN treatment using calculating modification, animal study, 3D magnetic mapping, optimal engineering design, measurement of right ventricular longitudinal peak systolic strain, multi-center/randomized clinical study, and molecular biological techniques. The achivement of the current study will provided a cluster of data showing the effect of PADN on patients with PH, and to identify the potential target of treating PH

肺动脉高压（PH）是心血管系统疾病中的癌症，主要死于右心衰。交感神经激活致能量代谢障碍，从而活化G蛋白偶联受体激酶（Grk2）、抑制肝脏激酶B1（LKB1）活性是右心衰发生的主要机制。但Grk2和LKB1在肺动脉重构中的作用机制及其相互关系尚未见报道。我们发明的肺动脉去神经术（PADN）能抑制肺动脉重构和右心衰，但存在如下问题：肺动脉交感神经变异程度大、环形头端的PADN导管不能适于大多数极度扩大的肺动脉、缺乏预测PADN疗效的可靠指标、PADN有效的分子生物学机制不明;申请人预实验发现Grk2和LKB1在肺动脉平滑肌细胞中相互连接、 去甲肾上腺素显著激活Grk2并抑制LKB1,PADN术后左右心室纵向应变率显著增加。为此，我们拟运用算法研究、动物实验、3D磁定位标测肺动脉交感神经、改良导管设计、临床多中心随机研究、右心室功能分析和激光共振能量转移等分子生物学技术，研究肺动脉交感神经标测、优化PADN导管设计、探索PADN术有效性的机制、建立预测PADN疗效的指标体系、寻找针对Grk2-LKB1新靶点的新型药物、实现PADN术转化应用，为PH的治疗提供技术新药物

肺动脉高压（PAH）是心血管疾病中的癌症，发病机制未明，寻找有效的药物靶点及技术治疗手段十分迫切。本项目组围绕研究目标，开展一系列基础及临床研究，取得主要进展及结果如下：1）发现PAH严重程度与GRK2水平呈正相关；抑制GRK2可有效降低肺动脉平滑肌细胞的增殖与迁移，显著改善肺动脉重构；作用机制包括：低氧刺激之后GRK2蛋白更加稳定，不易降解；GRK2通过调控YAP信号通路从而调节肺动脉平滑肌细胞增殖、迁移作用。2）研发肺动脉交感神经3D磁定位标测系统、建立经皮肺动脉去神经术（PADN）技术标准，利用自主研制射频消融导管及消融装置，并建立了“3点”消融靶点的去神经术的方法。3）实现PADN术及其器械的临床转化，初步证实了PADN治疗肺动脉高压患者的可行性及安全性。PADN-1临床研究表明在对药物治疗反应不佳的 IPAH 患者中，PADN 术可改善患者的功能和血流动力学；PADN-1 Phase II证实PADN改善肺动脉高压患者1年的血流动力学指标、活动耐量及心功能，减少PAH相关事件的发生及降低死亡率，而且PADN对不同类别的肺动脉高压患者都是安全及有效的；PADN-5 首次证实PADN在混合型毛细血管前后肺动脉高压(Cpc-PH)这类特殊Group II 肺动脉高压患者中的临床获益。综上，本项目主要揭示1）GRK2-YAP信号通路在PAH肺血管重构中的作用及机制；2）特异性阻断肺动脉交感神经治疗肺高压的有效性、安全性及机制，为肺动脉高压治疗提供新的药物干预靶点及技术手段。