Abstract
Hyperlipidemia induces vascular smooth muscle cell (VSMC) proliferation and phenotype switching from contractile to synthetic. This process is involved in arterial remodeling via the chemokine ligand 5 (CCL5)/chemokine receptor 5 (CCR5) pathway. Arterial remodeling is related to atherosclerosis or intimal hyperplasia. The purpose of this study was to evaluate whether pyrogallol-phloroglucinol-6,6-bieckol (PPB) from E. cava reduces VSMC proliferation and phenotype switching via the CCL5/CCR5 pathway. The CCL5/CCR5 expression, VSMC proliferation and phenotypic alterations were evaluated using a cell model of VSMC exposed in hyperlipidemia, and an animal model of mice fed a high-fat-diet (HFD). The expression of CCL5/CCR5 increased in both the cell and animal models of hyperlipidemia. Treatment with PPB decreased CCL5/CCR5 expression in both models. The expression of contractile markers of VSMCs, including alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), and smooth muscle protein 22 alpha (SM22α), were decreased by hyperlipidemia and restored after treatment with PPB. The silencing of CCR5 attenuated the effects of PPB treatment. VSMC proliferation and the intima-media thickness of the aortas, increased with HFD and decreased after treatment with PPB. The VSMC proliferation ratio and messenger ribonucleic acid (mRNA) expression of cell cycle regulatory factors increased in the in vitro model and were restored after treatment with PPB. PPB treatment reduced VSMC proliferation and phenotype switching induced by hyperlipidemia through inhibition of the CCL5/CCR5 pathway.
Highlights
Under normal homeostatic conditions with healthy vascular physiology, vascular smooth muscle cells (VSMCs) have low baseline levels of proliferation [1,2]
The purpose of our study was to evaluate whether PPB attenuates CCL5/chemokine receptor 5 (CCR5) expression induced by HFD and attenuates VSMC proliferation and reduced phenotype switching, which is a pathophysiological characteristic of atherosclerosis or intimal hyperplasia induced by HFD
PPB Reduced Expression of CCL5/CCR5 in VSMCs Treated With palmitic acid (PA) and in The Aortas of Mice
Summary
Under normal homeostatic conditions with healthy vascular physiology, vascular smooth muscle cells (VSMCs) have low baseline levels of proliferation [1,2]. In pathophysiological conditions, such as atherosclerosis or restenosis, after interventional therapy or intimal hyperplasia, Mar. Drugs 2020, 18, 393; doi:10.3390/md18080393 www.mdpi.com/journal/marinedrugs. Fully differentiated VSMCs are spindle-shaped, have contractile properties, and have a low proliferation rate [6]. The vascular wall remodeling process, which is induced by atherosclerosis or neointimal hyperplasia, leads to VSMC dedifferentiation or phenotype switching [6,7]. Phenotype switching induces VSMCs to change from a physiological contractile phenotype to a pathophysiological synthetic phenotype [8,9]. The synthetic VSMCs have rhomboid or epithelioid shape and exhibit a high proliferation rate and high rate of extracellular matrix (ECM) production [6,7]
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