Corin介导心房利钠肽参与心房颤动的分子机制研究

Atrial natriuretic peptide (ANP) is associated with the occurrence of atrial fibrillation (AF). Whether Corin, as the pro-ANP convertase, is participated in the occurrence of AF is unclear. Our previous experiments found that plasma Corin levels were significantly increased in AF patients; Corin and ANP were decreased in atria from mice infused with angiotensin II; the susceptibility to AF was increased in the patients with allele C of CORIN 3’untranslated region than that the patients with G allele, and miR-302c could down-regulate the expression of Corin. However, whether Corin is critical in the occurrence and development of AF and the role of the mechanism molecular are uncertain. In the present study, using human cardiomyocyte and human embryo kidney cell, Corin overexpression adeno-associated virus transfected mice and CORIN knockout mice, we aim to investigate the molecular mechanism of miR-302c regulating the expression of Corin, and clarify the role of Corin in regulating ANP on atrial fibrosis, inflammatory factors, ion channel and AF. This study will provide a new theoretical basis for elucidating the pathophysiology of AF and finding new therapeutic targets.

心房利钠肽（ANP）与心房颤动（房颤）的发生密切相关。活化ANP前体的丝氨酸蛋白酶Corin是否与房颤发生相关尚不明确。我们前期实验发现房颤患者血浆Corin水平明显升高，血管紧张素II灌注小鼠心房肌Corin和ANP表达均下降，CORIN 3’非翻译区基因多态性位点rs3749584 CC基因型房颤易感性显著增加，并且miR-302c能够下调Corin表达。但是，Corin是否为房颤发生发展的关键因素，以及调控Corin表达的分子机制不清楚。本项目拟在人心肌细胞及人胚肾细胞中，研究miR-302c调控Corin表达的分子机制；分别在Corin过表达9型腺相关病毒转染小鼠和CORIN基因敲除小鼠中，明确Corin通过调控ANP进而影响心肌纤维化、炎症因子表达、离子流改变参与房颤发生的分子机制，为阐明房颤发生的病理生理机制和寻找治疗新靶点提供新的理论依据。

心房利钠肽（ANP）与心房颤动（房颤）的发生密切相关。活化ANP前体的丝氨酸蛋白酶Corin是否与房颤发生相关尚不明确。本项目首次在小鼠HL1细胞中明确干扰Corin表达导致proANP裂解减少，ANP下降，使细胞内钙钠浓度升高，钾浓度减低，这可能是Corin下调导致房颤发生的分子机制；进一步验证miR-19b-1-5p能够特异性识别并下调Corin表达，是调控Corin参与房颤的miRNA；在AngII灌注小鼠中，AngII灌注Corin干扰rAAV9小鼠血压、房颤诱发率和房颤持续时间高于AngII灌注小鼠，AngII灌注miR-19b-1-5p干扰rAAV9小鼠血压、房颤诱发率和房颤持续时间低于AngII灌注小鼠，AngII灌注Corin干扰rAAV9+miR-19b-1-5p干扰rAAV9小鼠血压、房颤诱发率和房颤持续时间介于二者之间，在动物实验中进一步证实Corin能够减少房颤发生，miR-19b-1-5p能够下调Corin表达导致房颤发生；在191例行射频消融的房颤患者中发现，术后1d血浆Corin浓度较术前明显升高，可能与消融导致心肌细胞损伤后Corin释放增多相关，提示Corin是参与房颤发生发展的重要内分泌系统之一。目前小鼠实验病理、RT-PCR、WB等在进行中，正在随访房颤患者消融术后复发情况，明确术前、术后血浆Corin水平能否预测房颤消融成功率。通过本研究，提示Corin是房颤的保护因素，循环Corin水平可能作为预测房颤消融成功率的一个生物标志物转化应用于临床，对临床选择合适射频消融术患者，提高手术成功率有一定的指导意义。