Context: Conventional revascularization strategies for ischemic heart disease (IHD) are designed to prompt reperfusion of the coronary artery to salvage cardiomyocytes, but they may lead to myocardial reperfusion injuries.Objective: This work investigated the pro-angiogenic effect of Rotundic acid (RA) to provide the experimental basis for angiogenesis-mediated drug therapy of IHD.
Materials and methods:Human umbilical vein endothelial cells (HUVEC) were treated with vehicle or RA at 4, 8, 12, or 16μM for 24 h. A model of hindlimb ischemia was established using C57BL/6 mice. In sham-operated animals, only the femoral artery was isolated. Mice in the supplementation group were injected with RA (50 mg/kg body weight/day) for 7 days.Results: RA promoted cell proliferation, adhesion, migration and tube formation in the HUVECs in a dose-dependent manner. The ED50 of RA to improve cell adhesion is 8μM. In mice, RA promoted angiogenesis after ligation of the femoral artery and ameliorated the ischemic conditions. Intriguingly, more blood flow recovery was observed in the RA supplemented mice compared to the Vehicle-treated mice (0.85±0.05 vs. 0.71±0.10 on day 3; 0.94±0.10 vs. 0.75±0.08 on day 7). In HUVEC, RA increased the phosphorylation of STAT3 and JAK, which could be the mechanism by which RA mitigated IHD.
Conclusion:This is the first study that shows RA promotes angiogenesis under both normal and ischemic conditions. RA mitigates IHD potentially by activating the JAK-STAT3 pathway. Further clinical trials are warranted to verify the clinical implication.