Inhibitory Effects of Cilostazol on Proliferation of Vascular Smooth Muscle Cells (VSMCs) Through Suppression of the ERK1/2 Pathway

Abstract

A Rum Yoo and Seong-Ho Koh contributed equally to this work Aim: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca 2 levels, inhibiting platelet aggregation and inducing vasodilatation. Cilostazol is also known to have an inhibitory effect on the proliferation of VSMCs, but the anti-proliferative mechanism of cilostazol in VSMCs has not yet been established. In the present study, we investigated whether the anti-proliferative mechanism of cilostazol is associated with the suppression of extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways. Methods: To confirm the anti-proliferative effects of cilostazol on VSMCs, VSMCs were induced to proliferate by serum-induced mitogenesis and then were treated with cilostazol for 24 h. And, to investigate whether the anti-proliferative mechanism of cilostazol in VSMCs involves the suppression of the ERK and PI3K pathways, expression of the phosphorylated forms of ERK1/2, Raf, Akt, and glycogen synthase kinase (GSK)-3 were evaluated by western blot. Results: Cilostazol inhibited VSMC proliferation in a dose-dependent manner. Phosphorylated ERK1/2 and Raf were significantly reduced in a dose-dependent manner, whereas phosphorylated Akt and GSK-3 were not changed. Conclusion: These results suggest that suppression of the ERK pathway but not the PI3K pathway is an important mechanism in the anti-proliferative effect of cilostazol on VSMCs.

Downregulation of Quinone Reductase 2 Attenuates Vascular Smooth Muscle Cells Proliferation and Neointimal Formation in Balloon Injured Rat Carotid Artery

“…Increasing evidences have shown that ERK1/2 is a key enzyme involved in the regulation of cell proliferation [15,16,35,36]. Our study found that the ROS level and the phosphorylation of ERK1/2 significantly decreased in cultured rat VSMCs and balloon injured arterial walls after NQO2 siRNA treatment.…”

“…There is mounting evidence showing that extracellular signal-regulated kinase (ERK1/2) involves in the regulation of VSMCs proliferation [15][16]. Diverse stimuli, such as angiotensin II, TNF-α and fetal bovine serum (FBS) could increase the activity of NAD(P)H oxidase, a major source of reactive oxygen species (ROS) in vascular tissues.…”

Resveratrol inhibits angiotensin II-induced ERK1/2 activation by downregulating quinone reductase 2 in rat vascular smooth muscle cells

“…Increasing evidence has shown that ERK1/2 is a key enzyme involved in the regulation of cell proliferation[26]-[27]. Angiotensin II activates ERK1/2 and stimulates VSMC proliferation[28]-[30].…”

Transforming growth factor-β increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathways

“…Extracellular signal-related kinases 1 and 2 (ERK 1/2) are a subfamily of MAPKs that have been shown to regulate cellular processes such as transcription and proliferation. 14 Following binding and activation of a variety of growth factors, including PDGF, a cascade of events leads to dual phosphorylation of the two isoforms of ERK MAPK. Once phosphorylated, ERK MAPK becomes an active kinase which translocates to the nucleus where it has been shown to regulate transcription, specifically of genes such as cyclin D1 leading to cell-cycle progression through cytoplasmic sequestration of p27.…”