Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Cardiology Department, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
J Cell Physiol. 2020 Mar;235(3):2149-2160. doi: 10.1002/jcp.29119. Epub 2019 Aug 6.
miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of β-catenin, thus negatively regulating the Wnt/β-catenin pathway, which was confirmed by β-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/β-catenin-mediated EndMT.
miR-222 参与多种心血管疾病，但它对糖尿病引起的心脏重构的影响尚不清楚。本研究评估了 miR-222 在糖尿病小鼠心脏纤维化中的功能作用。链脲佐菌素（STZ）用于建立 1 型糖尿病小鼠模型。STZ 注射 10 周后，用 Ad-miR-222 静脉注射诱导 miR-222 的过表达。miR-222 的过表达减少了糖尿病小鼠的心脏纤维化并改善了心脏功能。机制上，miR-222 抑制了糖尿病小鼠心脏中的内皮到间充质转化（EndMT）。分离并培养小鼠心脏成纤维细胞和内皮细胞，并用高糖（HG）处理。miR-222 模拟物不影响 HG 诱导的成纤维细胞激活和功能，但抑制 HG 诱导的 EndMT 过程。miR-222 拮抗剂通过反义寡核苷酸抑制 HG 诱导的 EndMT。miR-222 调节β-catenin 的启动子区域，从而负调控 Wnt/β-catenin 通路，这通过β-catenin siRNA 得到证实。总之，我们的结果表明，miR-222 通过负调控 Wnt/β-catenin 介导的 EndMT 抑制糖尿病小鼠的心脏纤维化。
