Caffeic Acid Phenethyl Ester Inhibits PDGF-Induced Proliferation of Vascular Smooth Muscle Cells via Activation of p38 MAPK, HIF-1α, and Heme Oxygenase-1

Abstract

Hyperproliferation of vascular smooth muscle cells (VSMCs) is critically involved in the onset of atherosclerosis and restenosis. Although caffeic acid phenethyl ester (CAPE, 1), one of the main constituents of honeybee propolis, has been shown to exert a beneficial effect in models of vascular injury in vivo, detailed mechanistic investigations in vascular cells are scarce. This study has examined the antiproliferative activity of 1 in platelet-derived growth factor (PDGF)-stimulated primary rat aortic VSMCs and aimed to shed light on underlying molecular mechanisms. Compound 1 inhibited the proliferation of VSMCs upon exposure to PDGF in a dose-dependent manner by interfering with cell cycle progression from the G0/1- to the S-phase. Enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as stabilization of hypoxia-inducible factor (HIF)-1α and subsequent induction of heme oxygenase-1 (HO-1) could be identified as molecular events contributing to the observed growth arrest in PDGF-activated VSMCs upon exposure to 1.

Propolis Suppresses CdCl₂-Induced Cytotoxicity of COS7 Cells through the Prevention of Intracellular Reactive Oxygen Species Accumulation

“…Recently, it has been reported that the induction of HO-1 following activation of HIF-1α by propolis treatment played several physiological roles such as having antioxidative and anticancer properties. 8) In this study, treatment with CP extract increased nuclear accumulation of HIF-1α in a timedependent manner (Fig. 4C, i), and this accumulation was also determined when treated with BRP and BP extracts (Fig.…”

“…20,32,33) Recently, it has been reported that propolis and its component, CAPE, induce nuclear accumulation of HIF-1α in normoxia and increase the expression of HO-1 in vascular smooth muscle cells. 8) In this study, propolis extracts induced the nuclear accumulation of HIF-1α (Fig. 4C), indicating that propolis extract-inducible HO-1 mRNA was also mediated by the HIF-1α system and this elevation may be associated with the prevention of CdCl 2 -triggered ROS accumulation.…”

“…7) In addition, it has been reported that CAPE inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells through the induction of heme oxygenase-1 (HO-1), an anti-oxidative enzyme. 8) In contrast to their beneficial effects, CAPE has been known to induce apoptosis through inhibition of the activity of a transcriptional factor, nuclear factor-κB (NF-κB). 6) Cadmium (Cd) is an industrial and environmental pollutant.…”

Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

“…A number of molecules including α-lipoic acid, caffeic acid phenethyl ester, and nifedipine have been recognized for their anti-proliferative effects on VSMCs mediated by ROS reduction [20][21][22][23]. DPP-4 inhibitors such as sitagliptin, anagliptin, and alogliptin have been shown to reduce atherosclerotic lesions in apoE−/− mice by inhibiting proinflammatory responses and endothelial cell apoptosis, thereby preventing the cardiac malfunction associated with ROS production [9,10,24,25].…”

Emerging Roles of Propolis: Antioxidant, Cardioprotective, and Antiangiogenic Actions

“…Roos et al [82] evaluated the antiproliferative activity of CAFE, one of the major components of propolis and honey-derived products, in primary rat aortic VSMCs stimulated by platelet-derived growth factor (PDGF). CAFE inhibited proliferation of VSMCs upon exposure to PDGF in a dose-dependent manner, by interfering with cell cycle progression from the G0/1- to the S-phase.…”