“TGF-β/miRNA-433/多胺”反馈环路在糖尿病心肌纤维化中的作用及吡非尼酮干预研究

TGF-β1/Smad3通路活化是糖尿病心肌纤维化（DMF）发生的重要机制。miRNA-433不仅是该通路下游靶基因可被其激活促进肝、肾纤维化，还抑制鸟氨酸脱羧酶（ODC）/多胺通路、引起多胺耗竭，而多胺耗竭影响心肌细胞结构与功能并可放大TGF-β1/Smad3通路活性。我们前期研究发现，DMF动物心肌TGF-β1高表达并伴有miRNA-433上调和多胺减少，而吡非尼酮（Pir）可下调miRNA-433、改善DMF。由此推测，DMF过程中存在“TGF-β1/Smad3通路-miRNA-433-ODC/多胺通路”反馈环路，Pir通过下调miRNA-433抑制环路、改善DMF。项目拟以心肌成纤维细胞和db/db小鼠为对象，研究上述环路，并证明Pir通过下调miRNA-433抑制环路、改善DMF。项目的完成将提出DMF发生新机制及DMF防治新靶点，并为Pir临床应用提供新依据。

The TGF-β1/Smad3 pathway plays a major role in the development of diabetic myocardial fibrosis (DMF). MiRNA-433 not only is an important component of TGF-β1/Smad3-driven liver and renal fibrosis, but also an inhibitor of ornithine decarboxylase (ODC)/polyamine pathway. Moreover, polyamines play a fundamental role in myocardial cell structure and function, and their depletion may decrease cell growth and induce apoptosis. Also, depletion of intracellular polyamines induces the activation of TGF-β1/Smad3 pathway. Our previous studies indicated that TGF-β1 protein and miRNA-433 expressions were significantly increased and conversely, polyamines were found to be considerably decreased in diabetic db/db mice, which were accompanied by myocardial fibrosis. Pirfenidone, a new antifibrotic agent, attenuated these changes. In light of the previous studies and our findings, we hypothesize that there is a novel feedback circuits, “TGF-β1/Smad3 pathway-miRNA-433-ODC/polyamine pathway”, in the development of DMF, and pirfenidone maybe disturb this process by inhibiting miRNA-433 expression. To investigate our hypothesis, we will use a model of db/db mice to investigate this circuit loop in the development of DMF, and focus on the interventional effect of pirfenidone on the process. As a result, a new understanding of DMF mechanisms is put forward and miRNA-433 will be provided as a new target for DMF therapy. In addition, a novel anti-fibrosis mechanism of pirfenidone also will be clarified.