Inhibitory effects of vinpocetine on the progression of atherosclerosis are mediated by Akt/NF-κB dependent mechanisms in apoE-/- mice

• Published in: PloS one 2013-12, Vol.8 (12), p.e82509-e82509
• Main Authors: Zhuang, Jianhui, Peng, Wenhui, Li, Hailing, Lu, Yuyan, Wang, Ke, Fan, Fan, Li, Shuang, Xu, Yawei
• Format: Article
• Language: English
• Subjects: Adhesion; AKT protein; Animals; Apolipoprotein E; Apolipoproteins E - deficiency; Apoptosis; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Ca2+/calmodulin-dependent phosphodiesterase; Cancer; Cardiology; Cardiovascular disease; Cell proliferation; Cholesterol; Coronary vessels; Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism; Cytokines; Dephosphorylation; Disease Models, Animal; Disease Progression; Experiments; Extracellular matrix; Foam Cells - drug effects; Glucose; Humans; I-kappa B Proteins - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammatory response; Inhibition; Interleukin 6; Kinases; Laboratory animals; Lipids; Lipoproteins, LDL - metabolism; Low density lipoprotein; Macrophages; Male; Matrix metalloproteinase; Medicine; Mice; Mice, Knockout; Monocyte chemoattractant protein; Monocytes - drug effects; Monocytes - metabolism; Monocytes - pathology; Muscles; NF-kappa B - metabolism; NF-κB protein; Oxidative Stress; Oxygen; Phosphodiesterase; Phosphorylation; Plaque, Atherosclerotic - drug therapy; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Signal Transduction - drug effects; Smooth muscle; Studies; Tumor necrosis factor-α; Vinca Alkaloids - administration & dosage; Vinca Alkaloids - pharmacology; Vinpocetine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082509

Recent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE(-/-) mice and explore the underlying anti-atherogenic mechanisms in macrophages. Vinpocetine markedly decreased atherosclerotic lesion size in apoE(-/-) mice measured by oil red O. Masson's trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-α, IL-6, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 expression induced by ox-LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKα/β, IκBα phosphorylation and NF-κB activity induced by ox-LDL, and the inhibition of NF-κB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKα/β and IκBα phosphorylation. These results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-κB dependent pathway but independent of PDE1 blockade in macrophages.