血管钠肽下调Txnip抑制氧化应激在改善心衰中的作用及机制

Heart failure is the late outcome of a variety of diseases of the heart and lungs, looking for effective prevention of heart failure drugs and new measures, is one of the important issue in medicine. Effects of natriuretic peptide family on cardiovascular has attracted wide attention. The recently developed recombinant human brain natriuretic peptide, its half-life is very short, must continue administration of recombinant human brain natriuretic peptide, limit the large-scale clinical application. Therefore, preparation synthesis of highly efficient, long-term, cheap natriuretic peptide is one of the best ways to solve the problem. We and our cooperation unit invented artificially synthesized of vasonatrin peptide (VNP), which was good solubility, longer half-life, potential prospect of clinical application. We found that VNP could inhibit oxidative stress and reduce the myocardial ischemic injury. Latest pre-experiment has shown VNP can be adversely altered cardiac structure and function in the process of heart failure, at the same time reduce superoxide anion, and thioredoxin interacting protein (Txnip) expression. In this study, “VNP inhibition of Txnip expression -inhibition of oxidative stress -improve heart function” as the main line, aim to evaluate the role of VNP in the development of heart failure，revealing new mechanism of VNP delay the occurrence of heart failure. In order to provide experimental basis for the transition of clinical application VNP to treat heart failure.

心力衰竭是多种心肺疾病的晚期转归，寻找新的防治心衰有效药物和措施，是医学界的重要课题之一。钠尿肽家族对心血管的作用受到广泛关注，现已研发重组人脑钠肽，但其半衰期过短，须持续给药，临床应用价值受限。因此，合成高效、长效、廉价的钠尿肽类制剂是解决该问题的最佳方案之一。我们在国内首次成功合成了具有生物活性的血管钠肽(VNP)，其溶解度好，半衰期较长，但对心衰的影响及机制尚不清楚。我们前期发现VNP可抑制氧化应激、减轻缺血心肌损伤(AJP-H&C,2015)；最新预实验显示，VNP可延缓心衰过程中心脏结构功能的不利改变，同时减少超氧阴离子、硫氧还蛋白相互作用蛋白(Txnip)。本课题拟在此基础上，应用药理学与基因干预方法，以“VNP—抑制Txnip表达及氧化应激—改善心功能”为主线，阐明VNP对压力负荷性心衰发展的影响及机制，以期为VNP治疗心衰向临床应用过渡提供实验依据。

异丙肾上腺素引起的心肌肥厚可进一步发展为心力衰竭，造成死亡率升高。前期研究发现，外源性血管钠肽(VNP)对糖尿病大鼠心肌缺血/再灌注损伤具有心脏保护作用。然而在心肌肥厚中的作用仍不是很清楚。我们本次研究首先发现VNP可显著降低异丙肾上腺素诱导的心肌肥厚和心肌纤维化。此外，外源性VNP可有效抑制异丙肾上腺素诱导的心肌细胞凋亡和氧化应激的激活。且VNP的这种心肌保护作用通过cGMP-PKG信号通路的激活介导的，通过激动剂和拮抗剂的应用也证实了这些结果。另一方面，本课题也证实了VNP对压力负荷性心衰的作用是通过下调Txnip表达抑制氧化应激进而保护心肌结构和功能。本研究将为VNP治疗压力负荷性心肌损伤提供基础依据，并为临床防治心衰及其并发症提供新思路与新靶点。