The effects of peptides with estrogen-like activity on cell proliferation and energy metabolism in human derived vascular smooth muscle cells

Hormone replacement therapy (HRT) for post-menopausal symptoms in diabetes is associated with increased risk of coronary heart disease and stroke. Therefore, there is a need for new HRT with no adverse effects on diabetic post-menopausal women. We developed peptides as potential estrogen mimetic compounds and now we evaluated the effects of the most efficacious peptide; hexapeptide estrogen-mimetic peptide 1 (EMP-1) (VSWFFE) in comparison to estrogen (E₂) and peptides with weak activity A44 (KAWFFE) and A45 (KRAFFE) on modulation of cell proliferation of vascular smooth muscle cells (VSMC) growing in normal (ng) or high glucose (hg) concentrations. In ng EMP-1-like E₂ inhibited cell proliferation at high concentration, and stimulated at low concentration. EMP-1 did not affect E₂ stimulation of DNA, but inhibited E₂ inhibition of cell proliferation at high concentration. All effects by the combination of EMP-1 and E₂ were abolished at hg. A44-stimulated cell proliferation at all concentrations and A45 had no effect. When A44 was co-incubated with E₂ at both concentrations, DNA synthesis was stimulated, but abolished at hg. A45 abolished E₂ stimulation and inhibition of cell proliferation at both glucose concentrations. All peptides tested except A45-stimulated CK-specific activity at both glucose concentrations. In hg A44 stimulation of DNA was unaffected as well as its inhibition by EMP-1. EMP-1 and A44 similar to E₂- stimulated MAPK activity in ng or hg, suggesting similar mechanism of action. The results presented here suggest that EMP-1 provided it acts similarly in vivo can replace E₂ for treatment of post-menopausal women in hyperglycemia due to diabetes.