Novel Mechanisms of the Antiproliferative Effects of Amlodipine in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats

Lai, Yimu; Fukuda, Noboru; Su, Jin-Zi; Suzuki, Ryo; Ikeda, Yukihiro; Takagi, Hidenari; Tahira, Yoshiko; Kanmatsuse, Katsuo

doi:10.1291/hypres.25.109

Cited by 31 publications

(23 citation statements)

References 32 publications

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“…On the other hand, vascular SMCs proliferation and migration are other features of atherogenesis (10). It was reported that amlodipine inhibited exaggerated proliferation of vascular SMCs from spontaneously hypertensive rats (15). It was also showed that nifedipine inhibited platelet-derived growth factorinduced vascular SMCs migration via inhibition of activation of Pyk2/Src tyrosine kinase pathways (16).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells

et al. 2010

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Abstract. CV-159 is a unique dihydropyridine Ca2+ antagonist with an anti-calmodulin (CaM) action. A pathogenic feature of atherosclerosis is vascular inflammatory change. In the present study, we examined whether CV-159 exerts protective effects on smooth muscle inflammatory responses. After pretreatment of rat mesenteric arterial smooth muscle cells (SMCs) with CV-159 (0.1 -10 μ M, 30 min), TNF-α (10 ng/ml) was applied for 20 min or 24 h. CV-159 inhibited TNF (24 h)-induced vascular cell adhesion molecule (VCAM)-1 as determined by Western blotting. CV-159 inhibited TNF (20 min)-induced phosphorylation of Akt (Ser473) and NF-κ B p65 (Ser536). An Akt inhibitor, LY294002, and an NF-κ B inhibitor, pyrrolidine dithiocarbamate, inhibited TNF-induced VCAM-1. An antioxidant drug, N -acetyl-L -cysteine (NAC) inhibited TNFinduced VCAM-1. NAC also inhibited TNF-induced phosphorylation of Akt and NF-κ B. Furthermore, CV-159 inhibited TNF-induced reactive oxygen species (ROS) production as determined fluorometrically using dichlorodihydrofluorescein diacetate. A CaM inhibitor, W-7, and a calcium/ CaM-dependent protein kinase type II inhibitor, KN93, inhibited TNF-induced VCAM-1. W-7 and KN93 inhibited TNF-induced phosphorylation of Akt but not NF-κ B. The present results indicate that in vascular SMCs, CV-159 inhibits TNF-induced VCAM-1 through inhibition of NF-κ B and Akt phosphorylation. CV-159 prevents NF-κ B phosphorylation by inhibiting ROS, while it prevents Akt phosphorylation by inhibiting both ROS and CaM.

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Section: Discussionmentioning

confidence: 99%

“…Vascular smooth muscle cells (SMCs) proliferation and migration are also important features for the development of atherosclerosis. Recently, it was reported that amlodipine inhibited exaggerated proliferation of vascular SMCs from spontaneously hypertensive rats (15). Nifedipine was also shown to inhibit vascular SMCs migration (16 …”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells

et al. 2010

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“…Incubation of monocytic THP-1 cells with amlodipine significantly inhibited their adhesion to HUVECs in the presence of flow. Recent study results have indicated that certain calcium channel blockers might possess an ability to prevent atherosclerosis in vivo, 10 -12 and several in vitro findings have shown an inhibition of smooth muscle cell proliferation 13,14 and cytokine production 15,16 by amlodipine. Moreover, a recent prospective study of amlodipine that used a randomized evaluation method clearly suggested its dramatic efficacy in reducing cardiac events.…”

Section: Discussionmentioning

confidence: 99%

Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction

Morita

Shimokado

et al. 2003

Hypertension

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Abstract-Inflammatory responses play an important role in atherosclerosis. To critically assess the effect of dihydropyridines in inflammatory reactions, we conducted a monocyte-endothelial adhesion assay with monocytic THP-1 cells treated with amlodipine under flow conditions in vitro. THP-1 cells were incubated in the presence of amlodipine (10 mol/L) for 48 hours and then perfused over activated (interleukin-1␤, 10 U/mL, 4 hours) human umbilical vein endothelial cells. The adhesion of THP-1 cells was significantly reduced after amlodipine treatment (PϽ0.001); however, flow cytometric analysis reveled that the expression levels of integrins in THP-1 cells were not significantly altered. Furthermore, Western blotting analysis of THP-1 cell lysates revealed that translocation of RhoA from the cytosol to the membrane was significantly diminished after amlodipine treatment. In addition, activation of protein kinase C-␣ and -␤, as well as intracellular calcium influx, induced by phorbol 12-myristate 13-acetate, was diminished after amlodipine treatment. Pretreatment of THP-1 cells with calphostin C, a potent inhibitor of protein kinase C, significantly reduced THP-1 adhesion to vascular endothelium, whereas activation of ␤ 1 -integrin was reduced after amlodipine treatment in THP-1 cells, based on the immunoreactivity of an activation-specific antibody for ␤ 1 -integrin. Similar inhibitory effects were observed when we used freshly isolated peripheral blood mononuclear cells. These findings suggest a potential role for amlodipine in monocyte-endothelial interactions by modulation of protein kinase C-and RhoA-dependent mechanisms, which might account for its vascular protective effects. Key Words: calcium channel blockers Ⅲ cell adhesion molecules Ⅲ monocytes Ⅲ protein kinases Ⅲ signal transduction L -type calcium channel antagonists are widely used in the management of hypertension as well as coronary heart diseases, and an increasing number of reports support the therapeutic benefits of these compounds for patients with cardiovascular diseases. Recently, amlodipine, a Ca 2ϩ channel blocker, was shown to reduce the progression of atherosclerotic plaque formation in rabbit models, 1,2 suggesting its role in atherosclerosis. In one of those studies, amlodipine caused a significant and dose-dependent reduction in lesion formation in the thoracic aorta, 1 whereas in another, it exhibited an atheroprotective effect by acting as an antioxidant and reducing LDL uptake by the vessel wall, which consequently limited the size and extent of lesional areas. 3 These two findings have been proposed to show potential mechanisms for the antiatherosclerotic effect of amlodipine. In addition to those findings, the results of several in vitro studies also indicate that treatment with amlodipine enhances nitric oxide production in endothelial cells, 4 suggesting an anti-inflammatory role for the compound. In the present study, we attempted to elucidate the molecular mechanism responsible for the anti-inflammatory role of amlodipine by...

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“…The calcium channel blockade amlodipine has been shown to limit the progression of arteriosclerosis and atherosclerosis in animals and humans (37,38). Although the mechanisms underlying the direct protective effects of calcium channel blockades on endothelial cell injury are not fully understood, such vasoprotective effects as the amelioration of endothelial dysfunction (39,40) and decreases in the proliferation of vascular smooth muscle cells (41), oxidative stress (37,42), and inflammation (43), are at least in part independent of the blood pressure-lowering effects of these agents. The calcium channel blockade has been shown to ameliorate hypertension and improve NO production in the vasculature and kidneys.…”

Section: Introductionmentioning

confidence: 99%

Calcium Channel Blockades Exhibit Anti-Inflammatory and Antioxidative Effects by Augmentation of Endothelial Nitric Oxide Synthase and the Inhibition of Angiotensin Converting Enzyme in the NG-Nitro-L-Arginine Methyl Ester-Induced Hypertensive Rat Aorta: Vasoprotective Effects beyond the Blood Pressure-Lowering Effects of Amlodipine and Manidipine

et al. 2005

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Novel Mechanisms of the Antiproliferative Effects of Amlodipine in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats

Abstract: The calcium channel blocker amlodipine continues to be of interest due to its potential proven ability to hin-

Cited by 31 publications

References 32 publications

Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells

Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells

Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction

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