Tanshinone IIA (Tan IIA), isolated from the traditional Chinese herb Danshen, exhibits broad cardiovascular protective effects. However, the effect of Tan IIA on Homocysteine (Hcy)-induced proliferation of vascular smooth muscle cells (VSMCs) remains unknown. We herein determined whether Tan IIA exerted anti-proliferative effect in Hcy-treating VSMCs, and further investigated the underlying mechanism (miR-145/CD40 signaling). The results showed that Tan IIA significantly inhibited VSMCs proliferation induced by Hcy in a dose-dependent manner, and reversed the VSMCs injury as indicated by decreased KLF4 and increased Calponin expression. In view of the key role of miR-145 in VSMCs, we further explored the role of miR-145 on the protective effect of Tan IIA against Hcy-induced VSMCs proliferation. The miR-145 expression was down-regulated and its targeted gene CD40 was up-regulated in Hcy-treating VSMCs, while the Tan IIA reversed the effect of Hcy, suggesting the miR-145/CD40 may be involve in the protective effect of Tan IIA. To determine the speculation, miR-145 inhibitor was used to inhibit miR-145 expression. The results indicated that miR-145 inhibitor can suppress the protective effects of Tan IIA against Hcy-induced VSMCs proliferation. Collectively, present study demonstrates that Tan IIA inhibits Hcy-induced proliferation of VSMCs via miR-145/CD40 signaling. (C) 2019 Elsevier Inc. All rights reserved.