Danhong injection mobilizes endothelial progenitor cells to repair vascular endothelium injury via upregulating the expression of Akt, eNOS and MMP-9

Abstract

Backgroud: Endothelial progenitor cells (EPCs) have been characterized as one of the key effectors of endothelial healing. The effect of Danhong injection (DHI), the most widely prescribed Chinese medicine for coronary heart disease (CHD), on EPCs mobilization remains unclear.

Purpose: We aimed to assess the effect of DHI on EPCs mobilization to repair percutaneous coronary intervention (PCI) induced vascular injury, and to investigate the characteristics and potential mechanism of DHI on EPCs mobilization.

Method: Forty-two patients with CHD underwent PCI and received stent implantation were enrolled in a Phase II clinical trials. All patients received routine western medical treatment after PCI, patients of DHI group received DHI in addition. The levels of CECs, cytokines (vWF, IL-6, CRP) and EPCs were analyzed at baseline, post-PCI and after treatment. To investigate the characteristics of DHI on EPCs mobilization, 12 healthy volunteers received intravenous infusion of DHI once and the other 12 received for 7 days. EPCs enumeration were done at a series of time points. At last we tested the effect of DHI and three chemical constituents of DHI (danshensu; lithospermic acid, LA; salvianolic acid D, SaD) on EPCs level and expression of Akt, eNOS and MMP-9 in bone marrow cells of myocardial infarction (MI) mice.

Results: In the DHI group the angina symptoms were improved, the levels of cytokines and CECs were reduced; while EPCs population was increased after treatment. In the phase I clinical trials, EPCs counts reached a plateau phase in 9 h and maintained for more than 10 h after a single dose. After continuous administration, EPCs levels plateaued on the 3rd or 4th day, and maintain till 1 day after the withdrawal, then its levels gradually declined. DHI treatment induced a timely dependent mobilization of EPCs. DHI promoted EPCs mobilization via upregulating the expression of Akt, eNOS and MMP-9 in BM. LA and SaD have played a valuable role in EPCs mobilization.

Conclusion: These initial results demonstrated that DHI is effective in alleviating endothelial injury and promoting endothelial repair through enhancing EPCs mobilization and revealed the effect feature and possible mechanisms of DHI in mobilizing EPCs.

Keywords: Danhong injection; Endothelial progenitor cells; Expression of Akt, eNOS, and MMP-9; Mobilization; Vascular repair.