Deficiency of CD36 might be associated with insulin resistance and abnormal dynamics of long-chain fatty acids. Endothelin-1 (ET-1), which is synthesized and secreted by vascular endothelial cells, is the most potent endogenous vasoconstrictor known and also stimulates the proliferation of vascular smooth muscle cells (VSMCs) and thus is believed to play an important role in the development of various circulatory disorders, including hypertension and atherosclerosis. The aim of the present study was to investigate the regulatory effect of ET-1 on CD36 expression in cultured VSMCs. VSMCs were treated for different times (0-24 hours) with a fixed concentration (100 nM) of ET-1 or with different concentrations (0-100 nM) for a fixed time (24 h), then CD36 expression was determined using Western blots. CD36 expression was significantly decreased by ET in a time- and dose-dependent manner. This inhibitory effect was prevented by the ET_A receptor antagonist, BQ-610 (10 µM), but not the ET_B receptor antagonist, BQ-788 (10 µM). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the tyrosine kinase-mediated and mitogen-activated protein kinase-mediated pathways. The inhibitory effect of ET-1 on CD36 protein expression was blocked by inhibition of tyrosine kinase activation using genistein (100 µM) and by the ERK inhibitor, PD98059 (75 µM), but not the p38MAPK inhibitor, SB203580 (20 µM). In conclusion, we have demonstrated that ET-1, acting via the ET_A receptor, suppresses CD36 protein expression in VSMCs by activation of the tyrosine kinase and ERK pathways.