Abstract
BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.
Highlights
Atherosclerosis is a chronic inflammatory vascular disorder highly associated with endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory monocyte infiltration, lipid deposition, and vascular wall remodeling (Gimbrone and Garcia-Cardena, 2016)
peel polyphenols (PPP)/PU protect against oscillatory shear stress (OSS)-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects
The En face immunostaining revealed that treatment with PPP at 750 mg/kg reduced the areas of Oil Red O-stained plaques by 56% in mouse aortas, whereas PPP at 250 mg/kg and 500 mg/kg decreased the plaque areas by 23 and 37%, respectively
Summary
Atherosclerosis is a chronic inflammatory vascular disorder highly associated with endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory monocyte infiltration, lipid deposition, and vascular wall remodeling (Gimbrone and Garcia-Cardena, 2016). OSS-induced pro-inflammatory responses in ECs can elicit chemotaxis and adhesion of monocytes to the EC layers mediated by intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1), which further promotes atherosclerosis progression (Chiu et al, 2004). On the Abbreviations: OSS, oscillatory shear stress; PE, pomegranate extraction; PU, purified punicalagin; PPP, pomegranate peel polyphenols extraction; EC, endothelial cell; VSMC, vascular smooth muscle cell; HFD, high fat diet; BMPR, bone morphogenetic protein receptor; ICAM-1, intercellular adhesion molecule; VCAM-1, vascular cell adhesion molecule-1; TNF-α, tumor necrosis factor-α; MCP, monocyte chemotactic protein; TC, total cholesterol; TG, total triglyceride; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; L-NAME, L-N(G)-nitroarginine methyl ester; IL-6, interleukin-6; HPLC, high performance liquid chromatography. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms
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