The objective of the study is to calculate the role and underlying the molecular mechanisms of caveolin-1 (Cav-1) in atherosclerosis (AS). Cav-1 was mainly expressed in the endothelial cells of atherosclerotic lesions in both human patients and apolipoprotein E deficient (ApoE(-/-)) mice. Cav-1 deficiency (Cav-1(-/-)) attenuated high-fat diet (HFD)-induced atherosclerotic lesions in ApoE(-/-) mice, supported by the reduced aortic plaques. Cav-1(-/-) reduced the macrophage content and decreased the release of inflammation-related cytokines or chemokine in serum or abdominal aortas, accompanied with the inactivation of inhibitor kappa B kinase kappa (IKKO)/p65/1 kappa B alpha signaling pathway. Also, the activity of mitogen-activated protein kinases 7/c-Jun-N-terminal kinase (MKK7LINK) signaling was decreased by Cav-1(-/-). In addition, oxidative stress induced by HFD in ApoE(-/-) mice was alleviated by Cav-1(-/-). In response to HFD, Cav-1(-/-) markedly reduced triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDLC) and very low-density lipoprotein-cholesterol (VLDLC) in serum of HFD-fed ApoE(-/-) mice, whereas enhanced high-density lipoprotein-cholesterol (HDLC) contents. Consistent with these findings, haematoxylin and eosin (H&E) and Oil Red 0 staining showed fewer lipid droplets in the liver of Cav-1-deficient mice. Further, real time-quantitative PCR (RT-qPCR) analysis indicated that Cav-1(-/-)alleviated dyslipidemia both in liver and abdominal aortas of ApoE-/- mice fed with HFD. Cav-1 inhibition -induced attenuation of inflammatory response, oxidative stress and dyslipidemia were confirmed in vitro using mouse vascular smooth muscle cells (VSMCs) treated with ox-LDL. Surprisingly, the processes regulated by Cav-1-knockdown could be abolished through promoting JNK activation in ox-LDL-treated VSMCs. In conclusion, Cav-1 expression could promote HFD-induced AS in a JNK-dependent manner. (C) 2018 Published by Elsevier Inc.