Original ArticlePycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient MiceLiu, Rui MD, PhD*; Fan, Bin MD, PhD†; Cong, Huiying MBBS*; Ikuyama, Shoichiro MD, PhD‡; Guan, Haixia MD, PhD*; Gu, Jianqiu MD, PhD*Author Information *Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, P. R. China; †Department of Neurology, Shengjing Hospital, China Medical University, Shenyang, P. R. China; and ‡Department of Clinical Investigation and Department of Endocrine, Oita San-ai Medical Center, Oita, Japan. Reprints: Haixia Guan, MD, PhD or Jianqiu Gu MD, PhD, Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China (e-mail: [email protected] or [email protected]). Supported by the National Natural Science Foundation of China Youth Fund Project (Grant No. 81100216) and National Natural Science Foundation of China (Grant No. 81370905). The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: October 2016 - Volume 68 - Issue 4 - p 292-303 doi: 10.1097/FJC.0000000000000415 Buy Metrics Abstract Pycnogenol (PYC) is an extract from French maritime pine bark. Its antioxidative and anti-inflammatory effects have been shown to be beneficial for atherosclerosis. Here, we tested whether PYC could suppress high cholesterol and fat diet (HCD)-induced atherosclerosis formation in apolipoprotein E (apoE)-deficient mice. In our study, PYC suppressed oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation in peritoneal macrophages. Apolipoprotein E-deficient mice were orally administered PYC or a control solvent for ten weeks, and these mice were fed a standard diet or high cholesterol and fat diet during the latter eight weeks. Pycnogenol markedly decreased the size of atherosclerotic lesions induced by high cholesterol and fat diet compared with the nontreated controls. In addition, TLR4 expression in aortic sinus was stimulated by high cholesterol and fat diet feeding and was significantly reduced by PYC. A mechanistic analysis indicated that lipopolysaccharide (LPS) significantly increased expression of fatty acid binding protein (aP2) and macrophage scavenger receptor class A (SR-A), which were blocked by a JNK inhibitor. Furthermore, PYC inhibited the lipopolysaccharide-induced upregulation of aP2 and scavenger receptor class A via the JNK pathway. In conclusion, PYC administration effectively attenuates atherosclerosis through the TLR4-JNK pathway. Our results suggest that PYC could be a potential prophylaxis or treatment for atherosclerosis in humans. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.