PLC-β3在肾素原受体致肾性高血压大鼠心肌肥大的作用及其机制的研究

Myocardial hypertrophy caused by hypertension is a independent risk factor in cardiac sudden death. It is seriously harmful to human's life, but the mechanism remains unclear. Therefore, it is difficult to prevent and treat the disease. Recently, some researchers found that (pro)renin receptor,(P)RR,exists on cardiomyocytes and its activation causes myocardial hypertrophy. However,the mechanism of the post-receptor is not clear yet. Based on the national and international studies, we found that (P)RR expression increased in cardiomyocytes and there was a correlation between levels of (P)RR and PLC-β3 in renal hypertensive rats. PLC-β3 inhibitor reduced arterial blood pressure and myocardial hypertrophy. We hypothesize that (P)RR，combined with (pro)renin, activates PLC-β3 and its signal transduction system, and then results in intracellular protein proliferation and myocardial hypertrophy. To prove this hypothesis, we will examine the role of PLC-β3 in myocardial hypertrophy caused by (P)RR, and prove PLC-β3，IP3，Ca2+，DAG，PKC and others as the important factors in the signal transduction using yeast 2 hybrid method and so on. Thus, we will at the first time clarify the role and mechanism of (P)RR in myocardial hypertrophy and establish the base to produce the new targeted drugs for anti-myocardial hypertrophy.

高血压导致的心肌肥大是心脏猝死的独立危险因素，严重危害人类的生命，但其发生机制不明，因此很难进行有效的防治。最近有学者发现心肌细胞上存在肾素原受体(P)RR,其激活会引起心肌肥大，但受体后机制不清。在国内外研究的基础上，我们在试验中发现，肾性高血压大鼠心肌细胞上(P)RR表达增加，且与磷脂酶C（PLC-β3）表达呈相关关系，PLC-β3抑制剂有降低动脉血压及减缓心肌肥大的作用，推测(P)RR与肾素原结合后激活PLC-β3及其信号转导系统，引起细胞内蛋白增殖，导致心肌肥大。为证明这一假说，本课题拟应用肾性高血压大鼠，检测心脏组织PLC-β3 在(P)RR所致心肌肥大中的作用，应用酵母双杂交等方法，证明PLC-β3及IP3、Ca2+、DAG、PKC和其它有关因子是(P)RR信号转导的重要因子，将首次阐明PLC-β3 在(P)RR所致心肌肥大中的作用及其机制，为研制抗心肌肥大的靶点药物奠定基础。

【摘要】肾素-血管紧张素系统（Renin-angiotensin system, RAS）在高血压导致的心血管疾病中起重要作用。其中，新近发现的RAS新成分-肾素原受体（(pro)renin receptor, (P)RR）在高血压致心肌肥大中的作用受到国内外科学界的高度重视。我们针对RAS及(P)RR在高血压心肌肥大的作用及其机制问题进行了深入研究。首先，我们研究了RAS在肾性高血压心肌损害中的作用，发现了与血管紧张素转换酶抑制剂Enalapril不同，血管紧张素II阻断剂Losartan对这种心肌损害独特的治疗作用；随后，首次发现了肾积水导致心肌肥大损害以及RAS在心肌损害中的作用；应用肾性高血压动物模型，首次发现了磷脂酶C-β3（PLC-β3）与(P)RR在心肌组织表达同步升高，(P)RR激活PLC-β3，进而激活PKC-ERK1/2-Raf-1信号通路，导致心肌细胞肥大。我们首次提出PLC-β3 -PKC-ERK1/2-Raf-1信号通路在(P)RR致高血压心肌肥大中的作用。上述对RAS的深入探讨与实验发现获得了一系列研究成果，为研制抗高血压致心肌损害的靶点药物提供了理论基础。