Anti-atherosclerotic effects of genistein in preventing ox-low-density lipoprotein-induced smooth muscle-derived foam cell formation via inhibiting expression and L-Ca channel currents.

BACKGROUND

Atherosclerosis (AS) is associated with inflammation and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Genistein may curtail the migration of VSMCs. Therefore, explorations are required to determine the molecular mechanism of genistein in AS. In this context, animal and cell models were developed to ascertain mechanisms of genistein in AS by modulating VSMC activities.

METHODS

Genistein treatment and ectopic expression of lectin-like oxidized LDL receptor-1 () were conducted in high-fat diet-induced AS rats, followed by analyses of atherosclerotic plaque lesion areas and lipid deposition using Oil Red O and hematoxylin and eosin (HE) staining. The isolated VSMCs were stimulated with oxidized low-density lipoprotein (ox-LDL). Following genistein treatment combined with gain- and loss-of-function experiments in ox-LDL-exposed VSMCs, viability, migration, intracellular lipid deposition, intracellular cholesterol content, and L-type calcium (L-Ca) channel currents were assessed using Cell Counting Kit-8 (CCK-8), scratch test, Oil Red O staining, enzymatic colorimetry, and patch-clamp experiments, respectively. Western blot analysis was performed to evaluate the protein expression of proto-oncogene, non-receptor tyrosine kinase (), calcium voltage-gated channel subunit alpha1 C (), and .

RESULTS

Genistein treatment counteracted upregulated phosphorylation, and expression, and L-Ca channel currents in aortic tissues of AS rats and ox-LDL-exposed VSMCs. Genistein deceased L-Ca channel currents by downregulating , and augmented expression by acting on the L-Ca channel subunit . The ox-LDL-induced VSMC proliferation, migration, and foaming of VSMCs were reduced by genistein treatment, silencing , , or , or suppressing L-Ca channels. Genistein treatment diminished atherosclerotic plaque lesion formation and lipid deposition, and these results were annulled by upregulating .

CONCLUSIONS

Collectively, genistein might block the // axis to impede ox-LDL-induced VSMC proliferation, migration, and foaming and alleviate AS formation.