姜黄素/Cdr1as/miR-7a在小鼠心肌梗死后心脏纤维化中的作用及其机制研究

The interstitial fibrosis post-Myocardial infarction (MI) eventually leads to left ventricular remodeling and heart failure. We considered attenuating of the interstitial fibrosis was a core mechanism in cardiac function after MI. We previously found miR-7a offered protection by reducing fibrosis ,minimizing cardiac remodeling and improving cardiac function after MI, under the mechainism of targeting its targets Sp1 in cardiomyocytes (CMs) and cardiac fibroblasts (CFs).Further, miR-7a is essential for the cardiac protection of Curcumin post-MI . Cdr1as (or CiRS-7), was one of well-identified circular RNAs (circRNAs) and defined as miR-7 sponge or inhibitor. We lately found Cdr1as was up-regualted in angiotensin Ⅱ (ANG Ⅱ)-treated CMs and CFs, as well as in the mouse model that suffered ligation of left anterior descending coronary artery (LAD) in the heart. Overexpression of Cdr1as increased Sp1 and collagen Ⅰ expression, which could be reversed by miR-7a co-overexpression both in vivo and in vitro. On the basis of above, we raise a hypothesis that Cdr1as could regulate the function of miR-7a in CFs and play an essential role in the fibrosis after MI,while mediating the function of Curcumin . We will apply models of the ligation of LAD in the mice and ANG Ⅱ-treated CFs with/without Cdr1as/miR-7a intervention, together with/without treatment of Curcumin to carry out the study. Pathological, molecular biological methods and cardiac catheter will be used to investigate the possible regulatory mechanism of Curcumin/Cdr1as/miR-7a in cardiac fibrosis. Hopefully this study would provide a new perspective and evidence for the treatment of fibrotic cardiovascular disease.

减轻心脏纤维化是改善心肌梗死后心脏重构的重难点。我们既往研究发现miR-7a通过调控靶基因Sp1和胶原I，减轻小鼠心梗后心脏纤维化，有效改善心脏功能，并介导了姜黄素对心梗小鼠的心肌保护作用。Cdr1as是一种循环RNA，有miR-7抑制剂的作用。我们前期研究发现梗死心肌组织中Cdr1as的表达增高，上调其表达Sp1和胶原I表达增多；在血管紧张素Ⅱ刺激的心肌成纤维细胞中，Cdr1as的表达同样增高，过表达Cdr1as可抑制miR-7a，且刺激Sp1和胶原I表达；miR-7a mimics则可部分拮抗上述作用。因此我们提出Cdr1as通过作用于miR-7a及其下游靶基因，参与调控心肌梗死后心脏纤维化，并介导姜黄素的心脏保护作用。我们将从体内体外两个方面，联合病理学与分子生物学技术、心脏导管等技术，围绕姜黄素/Cdr1as/miR-7a在心梗后心脏纤维化进程中的作用及可能机制展开研究。

减轻心脏纤维化是改善心肌梗死后心脏重构的重难点。我们前期发现miR-7a通过调控Sp1和胶原I,减轻小鼠心梗后心脏纤维化,有效改善心脏功能，并介导了姜黄素对心梗小鼠的心肌保护作用。Cdr1as是一种循环RNA，有miR-7抑制剂的作用。我们发现梗死心肌组织中Cdr1as的表达增高，上调其表达Sp1和胶原I表达增多；在血管紧张素II刺激的心肌成纤维细胞中，Cdr1as的表达同样增高，过表达Cdr1as可抑制miR-7a,且刺激Sp1和胶原I表达；miR-7a mimics则可部分拮抗上述作用。因此我们从体内体外两个方面,联合病理学与分子生物学技术, 围绕姜黄素/Cdr1as/miR-7a在心梗后心脏纤维化进程中的作用及可能机制展开研究，发现Cdr1as通过调控miR-7a及其下游靶基因，参与调控心肌梗死后心脏纤维化，并介导姜黄素的心脏保护作用。