Cilostazol Inhibits Monocytic Cell Adhesion to Vascular Endothelium Via Upregulation of cAMP

Mori, Daisuke; Ishii, Hiroko; Kojima, Chiari; Nitta, Noriko; Nakajima, Katsuyuki; Yoshida, Masayuki

doi:10.5551/jat.e492

Cited by 16 publications

(11 citation statements)

References 25 publications

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“…In contrast, it has not yet been established whether cAMP is associated with VSMC proliferation. In the current study, we showed that increasing the intracellular cAMP level by treating cells with cilostazol 17,18) inhibited FBS-induced VSMC proliferation in a dose-dependent manner (Fig. 2, 3).…”

Section: Discussionmentioning

confidence: 90%

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

Yoo

Koh

Cho

et al. 2010

JAT

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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.

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Section: Discussionmentioning

confidence: 90%

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

Yoo

Koh

Cho

et al. 2010

JAT

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“…For the effects on leukocyte interaction, HUVECs were transfected with non-targeting, kindlin-2 or kindlin-3 siRNA, plated in a 24-well tissue culture vessel, and treated with or without 10 ng/ml of TNF-α. Calcein-AM-labeled THP-1 monocytoid cells, a cell line that has been used extensively to study the interaction of cells of the monocytoid lineage with endothelial cells (30–32) were then coincubated with HUVEC for 1 h, and adherence of THP-1 cells was determined by measuring fluorescence intensity. There was minimal adhesion of THP-1 cells to HUVEC that had not been treated with TNF-α.…”

Section: Resultsmentioning

confidence: 99%

The Integrin Co-activator Kindlin-3 Is Expressed and Functional in a Non-hematopoietic Cell, the Endothelial Cell

Białkowska

Błędzka

et al. 2010

Journal of Biological Chemistry

103

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Integrin activation is crucial for numerous cellular responses, including cell adhesion, migration, and survival. Recent studies in mice have specifically emphasized the vital role of kindlin-3 in integrin activation. Kindlin-3 deficiency in humans also has now been documented and includes symptoms of bleeding, frequent infections, and osteopetrosis, which are consequences of an inability to activate β1, β2, and β3 integrins. To date, kindlin-3 was thought to be restricted to hematopoietic cells. In this article, we demonstrate that kindlin-3 is present in human endothelial cells derived from various anatomical origins. The mRNA and protein for KINDLIN-3 was detected in endothelial cells by reverse transcription-PCR and Western blots. When subjected to sequencing by mass spectrometry, the protein was identified as authentic kindlin-3 and unequivocally distinguished from KINDLIN-1 and KINDLIN-2 or any other known protein. By quantitative real time PCR, the level of kindlin-3 in endothelial cells was 20–50% of that of kindlin-2. Using knockdown approaches, we show that kindlin-3 plays a role in integrin-mediated adhesion of endothelial cells. This function depends upon the integrin and substrate and is distinct from that of kindlin-2. Formation of tube-like structures in Matrigel also was impaired by kindlin-3 knockdown. Mechanistically, the distinct functions of the kindlins can be traced to differences in their subcellular localization in integrin-containing adhesion structures. Thus, the prevailing view that individual kindlins exert their functions in a cell type-specific manner must now be modified to consider distinct functions of the different family members within the same cell type.

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“…Crucially, cAMP also induces vascular protective effects in ECs, where it promotes barrier function 7 , and inhibits inflammation 8 , ROS generation 9 and monocyte adhesion 10 . It is not surprising, therefore, that altered or aberrant cAMP signalling has been linked to numerous vascular pathologies, including angioplasty restenosis 11 , late vein graft failure 12 and atherogenesis 13 .…”

Section: Introductionmentioning

confidence: 99%

Divergent Regulation of Actin Dynamics and Megakaryoblastic Leukemia-1 and -2 (Mkl1/2) by cAMP in Endothelial and Smooth Muscle Cells

Smith

Hudson

Kimura

et al. 2017

Sci Rep

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Proliferation and migration of vascular smooth muscle cells (VSMCs) or endothelial cell (ECs) promote or inhibit, respectively, restenosis after angioplasty, vein graft intimal thickening and atherogenesis. Here we investigated the effects of cAMP-induced cytoskeletal remodelling on the serum response factor (SRF) co-factors Megakaryoblastic Leukemia-1 and -2 (MKL1 and MKL2) and their role in controlling VSMC and EC proliferation and migration. Elevation of cAMP using forskolin, dibutyryl-cAMP (db-cAMP), BAY60-6583 or Cicaprost induced rapid cytoskeleton remodelling and inhibited proliferation and migration in VSMCs but not EC. Furthermore, elevated cAMP inhibited mitogen-induced nuclear-translocation of MKL1 and MKL2 in VSMCs but not ECs. Forskolin also significantly inhibited serum response factor (SRF)-dependent reporter gene (SRE-LUC) activity and mRNA expression of pro-proliferative and pro-migratory MKL1/2 target genes in VSMCs but not in ECs. In ECs, MKL1 was constitutively nuclear and MKL2 cytoplasmic, irrespective of mitogens or cAMP. Pharmacological or siRNA inhibition of MKL1 significantly inhibited the proliferation and migration of VSMC and EC. Our new data identifies and important contribution of MKL1/2 to explaining the strikingly different response of VSMCs and ECs to cAMP elevation. Elucidation of these pathways promises to identify targets for specific inhibition of VSMC migration and proliferation.

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Cilostazol Inhibits Monocytic Cell Adhesion to Vascular Endothelium Via Upregulation of cAMP

Cited by 16 publications

References 25 publications

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

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

The Integrin Co-activator Kindlin-3 Is Expressed and Functional in a Non-hematopoietic Cell, the Endothelial Cell

Divergent Regulation of Actin Dynamics and Megakaryoblastic Leukemia-1 and -2 (Mkl1/2) by cAMP in Endothelial and Smooth Muscle Cells

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