Anti-Atherosclerotic Effect of Hibiscus Leaf Polyphenols against Tumor Necrosis Factor-alpha-Induced Abnormal Vascular Smooth Muscle Cell Migration and Proliferation.

Cheng-Chung Chou,Chi-Ping Wang,Hui-Hsuan Lin,Jing-Hsien Chen

doi:10.3390/antiox8120620

Abstract

The proliferation and migration of vascular smooth muscle cells (VSMCs) are major events in the development of atherosclerosis following stimulation with proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α). Plant-derived polyphenols have attracted considerable attention in the prevention of atherosclerosis. Hibiscus leaf has been showed to inhibit endothelial cell oxidative injury, low-density lipoprotein oxidation, and foam cell formation. In this study, we examined the anti-atherosclerotic effect of Hibiscus leaf polyphenols (HLPs) against abnormal VSMC migration and proliferation in vitro and in vivo. Firstly, VSMC A7r5 cells pretreated with TNF-α were demonstrated to trigger abnormal proliferation and affect matrix metalloproteinase (MMP) activities. Non-cytotoxic doses of HLPs abolished the TNF-α-induced MMP-9 expression and cell migration via inhibiting the protein kinase PKB (also known as Akt)/activator protein-1 (AP-1) pathway. On the other hand, HLP-mediated cell cycle G0/G1 arrest might be exerted by inducing the expressions of p53 and its downstream factors that, in turn, suppress cyclin E/cdk2 activity, preventing retinoblastoma (Rb) phosphorylation and the subsequent dissociation of Rb/E2F complex. HLPs also attenuated reactive oxygen species (ROS) production against TNF-α stimulation. In vivo, HLPs improved atherosclerotic lesions, and abnormal VSMC migration and proliferation. Our data present the first evidence of HLPs as an inhibitor of VSMC dysfunction, and provide a new mechanism for its anti-atherosclerotic activity.

Highlights

Atherosclerosis is considered a chronic inflammatory process and involves a complex pathophysiological effect, including endothelial dysfunction, low-density lipoprotein (LDL) oxidation, foam cell formation, and vascular smooth muscle cell (VSMC) proliferation and migration at different stages of this disease [1,2]
Because matrix metalloproteinase (MMP) break down components of extracellular matrix (ECM), which is a crucial role in the process of VSMC migration [7,8], the effect of TNF-α on MMP activities was tested by gelatin zymography in serum-free conditioned medium to identify the contribution of MMP-2 or MMP-9 to the pro-migratory ability of TNF-α
Hibiscus leaf polyphenols (HLPs) is speculated to play a role in TNF-α antagonist, which contributes to inhibiting

Summary

Introduction

Atherosclerosis is considered a chronic inflammatory process and involves a complex pathophysiological effect, including endothelial dysfunction, low-density lipoprotein (LDL) oxidation, foam cell formation, and vascular smooth muscle cell (VSMC) proliferation and migration at different stages of this disease [1,2]. Elevated plasma LDL concentration contributes to the initiation of atherosclerosis [3]. Oxidized LDL triggers endothelial cells to release chemokines in contribution to recruitment of monocytes, resulting in the transformation of the lipid-laden macrophages into. VSMC transforms and proliferates into foam cells, and the accumulation of foam cells leading to fatty streaks results in the formation of atherosclerotic plaques [2]. Inhibition of abnormal VSMC migration and proliferation is an attractive strategy for clinical therapy of atherosclerosis and restenosis after percutaneous coronary interventions

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