Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.
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.
*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.
Rui
R
Liu
Bin
B
Fan
Huiying
H
Cong
Shoichiro
S
Ikuyama
Haixia
H
Guan
Jianqiu
J
Gu
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010936:Plant Extracts; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D005419:Flavonoids; D010936:Plant Extracts; D010975:Platelet Aggregation Inhibitors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C024070:pycnogenols