Arterial and venous smooth-muscle cells differ in their responses to antiproliferative drugs

Kim, Seung Jung; Masaki, Takahisa; Leypoldt, John K.; Kamerath, Craig D.; Mohammad, Sameer; Cheung, Alfred K.

doi:10.1016/j.lab.2004.06.002

Cited by 37 publications

(29 citation statements)

References 26 publications

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“…In addition, adenosine and selective adenosine A 2 receptor agonists have been shown to inhibit the growth of aortic SMCs in normal and streptozotocin-induced diabetic rats (10,19,27,40). Recent studies have provided evidence that dipyridamole, which is a putative ENT-1 inhibitor and increases extracellular adenosine concentration, can inhibit vascular SMC proliferation (20,23). These studies suggest the relevance of adenosine in vascular functions and the role of nucleoside transporters in adenosine homeostasis.…”

Section: Discussionmentioning

confidence: 98%

d-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells

Leung

Man

Tse³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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nucleoside transporter; diabetes ADENOSINE MODULATES CELLULAR functions via G protein-coupled receptors to protect cells and organs and is released in response to cell injury and stress. For instance, adenosine levels in blood and interstitial fluid increase during hypoxia and ischemia. Increased extracellular adenosine causes vasodilation by acting through A 2 adenosine receptors on vascular smooth muscle cells (SMCs) (5, 31) and, thus, increases blood flow and oxygenation. Adenosine inhibits platelet aggregation (33), decreases heart rate (14), and antagonizes the stimulatory effects of catecholamines (37). Because of these important functions of adenosine as a negative-feedback modulator of cell and organ energy demand and consumption and as a celland organ-protective agent, it is known as a "retaliatory metabolite" (25). Recent reports also showed that adenosine released during preconditioning by short periods of ischemia followed by reperfusion induces cardioprotection to a subsequent sustained ischemia (17). This effect is mediated in part by activation of A 1 and A 3 adenosine receptors in cardiomyocytes and involves PKC and mitochondrial ATP-sensitive K ϩ channels (24).Nucleoside transporters fine-tune the local concentrations of adenosine in the vicinity of adenosine receptors. Two major classes of nucleoside transporters in mammalian cells have been characterized by Na ϩ dependence (16). The equilibrative nucleoside transporters (ENTs) are facilitated-diffusion systems and are Na ϩ independent. They are further subdivided into two types on the basis of their sensitivities to inhibition by nitrobenzylmercaptopurine riboside (NBMPR) (4, 43). ENT-1 is potently inhibited by nanomolar concentrations of NBMPR, but ENT-2 is resistant to NBMPR up to 1 M. ENT-1 and ENT-2 are broadly selective, accepting purine and pyrimidine nucleosides, but ENT-2 also transports nucleobases such as hypoxanthine (6,26,46). In contrast, the concentrative nucleoside transporters (CNTs) are Na ϩ dependent. CNT-1 is pyrimidine selective (36), CNT-2 is purine selective (42), and CNT-3 is broadly selective (35,41).Diabetes mellitus is a major risk factor for cardiovascular diseases. Because adenosine inhibits growth of vascular SMCs (10,11,12,13) and nucleoside transporters are involved in adenosine homeostasis, in the present study, we characterized the nucleoside transport systems in cultured human aortic SMCs (HASMCs). We also determined the effect on adenosine transport of long-term exposure of cells to 25 mM D-glucose, a condition that mimics hyperglycemia of diabetes. MATERIALS AND METHODSCulture of HASMCs. HASMCs were obtained from American Type Culture Collection (Manassas, VA) and cultured in DMEM (containing 5 mM D-glucose) supplemented with 10% (vol/vol) fetal bovine serum, 100 U/ml penicillin, and 100 g/ml streptomycin at 37°C in 95% air-5% CO 2. All experiments were carried out with cells from passages 6 to 14. At 48 h before uptake study and mRNA and protein isolation, cells were incubated in serum-free DMEM. To study t...

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Section: Discussionmentioning

confidence: 98%

d-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells

Leung

Man

Tse³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…The IC 50 s of each drug in each experiment (n = 8–10) were determined separately. These values were then averaged for each drug and compared [22]. …”

Section: Methodsmentioning

confidence: 99%

Clopidogrel Effectively Suppresses Endothelial Microparticle Generation Induced by Indoxyl Sulfate via Inhibition of the p38 Mitogen-Activated Protein Kinase Pathway

Ryu

Kim²

2011

Blood Purif

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Background/Aims: Endothelial microparticles (EMPs) are closely associated with vascular dysfunction. We investigated the effects of several drugs on EMP generation in human umbilical vein endothelial cells (HUVECs), and the involvement of the mitogen-activated protein kinase (MAPK) in EMP generation. Methods: CD31+CD42-EMP counts were measured by flow cytometry in supernatants of HUVECs incubated with indoxyl sulfate. The EMP responses to losartan, lovastatin, clopidogrel, and mesoglycan were examined. We then measured the effects of MAPK inhibitors on EMPs. Results: (1) Indoxyl sulfate induced EMP release in HUVECs in a dose-dependent fashion; (2) all drugs (10–50 µM) inhibited EMP generation induced by indoxyl sulfate, with clopidogrel being the most effective; (3) the p38 MAPK inhibitor suppressed EMP generation induced by indoxyl sulfate, and (4) clopidogrel significantly suppressed MAPK signaling activated by indoxyl sulfate, with the most potency on p38. Conclusion: The p38 signaling involves EMP generation induced by indoxyl sulfate and is effectively suppressed by clopidogrel.

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“…Docetaxel is approximately 2-fold more potent than paclitaxel as a tubulin assembly promoter and microtubule stabilizer (11). Paclitaxel has been shown in numerous studies to exhibit beneficial effects on the control of atherosclerosis and heart disease (12,13). Thus, docetaxel may also affect vascular diseases through the regulation of smooth muscle cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Docetaxel on Platelet-Derived Growth Factor (PDGF)-BB–Induced Proliferation of Vascular Smooth Muscle Cells Through Blocking PDGF-Receptor β Phosphorylation

et al. 2011

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Abstract. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is an important pathogenic factor for vascular disorders such as atherosclerosis and restenosis after angioplasty. The present study was designed to investigate the inhibitory effects of docetaxel on VSMC proliferation, as well as the molecular mechanism of this inhibition. Docetaxel at 10, 20 and 40 μM significantly inhibited both the proliferation and the DNA synthesis of fetal bovine serum (FBS)-and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs in a concentration-dependent manner. In accordance with these findings, docetaxel blocked the FBS-and PDGF-BB-induced progression of synchronized cells through the G0/G1 phase of the cell cycle. Docetaxel also decreased the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma protein, and proliferative cell nuclear antigen in PDGF-BB-stimulated VSMCs. Docetaxel significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and phospholipase C-γ1, downstream molecule in the PDGF-BB signaling pathway. Docetaxel suppressed the phosphorylation of PDGF receptor (PDGF-R) β, the upstream molecule in PDGF-BB signaling cascade, suggesting that the inhibitory effect of docetaxel on the proliferation of VSMCs may occur by blocking PDGF-Rβ phosphorylation. Thus, docetaxel may be a potential antiproliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

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Arterial and venous smooth-muscle cells differ in their responses to antiproliferative drugs

Cited by 37 publications

References 26 publications

d-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells

d-Glucose upregulates adenosine transport in cultured human aortic smooth muscle cells

Clopidogrel Effectively Suppresses Endothelial Microparticle Generation Induced by Indoxyl Sulfate via Inhibition of the p38 Mitogen-Activated Protein Kinase Pathway

Inhibitory Effects of Docetaxel on Platelet-Derived Growth Factor (PDGF)-BB–Induced Proliferation of Vascular Smooth Muscle Cells Through Blocking PDGF-Receptor β Phosphorylation

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