CV-159, a Unique Dihydropyridine Derivative, Prevents TNF-Induced Inflammatory Responses in Human Umbilical Vein Endothelial Cells

Usui, Tatsuya; Yamawaki, Hideyuki; Kamibayashi, Masato; Okada, Muneyoshi; Hara, Yukio

doi:10.1254/jphs.10033fp

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…In the previous study, we showed that an antioxidant drug, N-acetyl l-cysteine inhibited TNF-induced expression of VCAM-1 and e-selectin, as well as activation of Akt, JNK, and p38, in cultured SMCs or endothelial cells. 14,15 In addition, we confirmed that the inhibitor of Akt, JNK, or p38 prevented TNF-induced expression of VCAM-1 or e-selectin. Collectively, our results indicate that DAPK3 mediates TNFinduced inflammation via induction of proinflammatory molecules (VCAM-1, e-selectin, and COX-2) through activation of ROS-dependent signals in cultured SMCs and endothelial cells.…”

Section: October 2012supporting

confidence: 66%

Death-Associated Protein Kinase 3 Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

et al. 2012

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C almodulin (CaM) is recognized as a key regulatory molecule for diverse biological functions, such as muscular contraction.1 In addition, a recent study demonstrated that CaM-dependent protein kinases, such as CaM-dependent protein kinase II, may regulate hypertension through the mechanisms including promotion of vascular smooth muscle hypertrophy. 2 In the previous study, we compared expression levels of several CaM-related proteins with almost unknown functions in vasculature. As a result, we demonstrated that protein expression of eukaryotic elongation factor 2 kinase (also known as CaM-dependent protein kinase III), histone deacetylase 4, and death associated protein kinase (DAPK) 3 increased in the mesenteric artery from spontaneously hypertensive rats (SHRs) compared with Wistar Kyoto rats (WKYs). 3 In the recent study, we also showed that histone deacetylase 4 promotes reactive oxygen species (ROS)-dependent vascular inflammation and mediates the development of hypertension in SHRs. 4 However, it remains to be clarified how DAPK3, might affect vascular patholophysiology and control the development of hypertension. The DAPK protein has been considered as a Ca 2+ /CaMregulated serine/threonine kinase that mainly mediates cell death. 5 The DAPK protein consists of multiple domains, including an N-terminal kinase domain (known as a Ca 2+ /CaM regulatory region), ankyrin repeats, a cytoskeleton binding region, and a C-terminal death domain.6 Various stimulation-induced intracellular calcium spikes promote the CaM binding to the CaM regulatory region of DAPK, which in turn activates DAPK.7 Five protein kinases, including DAPK1, DAPK2, DAPK3 (also known as Zipper-interacting protein kinase), DAPK-related apoptosis-inducing protein kinase 1, and DAPK-related apoptosis-inducing protein kinase 2, are known as DAPK family proteins.8 DAPK1, DAPK2, and DAPK3 are all ubiquitously expressed in various tissues from mice and rats.6 Recently, the functions of DAPK3 were gradually clarified. The mutation of DAPK3 Abstract-Death-associated protein kinase (DAPK) is a Ca 2+ /calmodulin-regulated serine/threonine kinase that mediates cell death. Our recent study demonstrated that DAPK3 protein increases in the mesenteric artery from spontaneously hypertensive rats compared with Wistar Kyoto rats. Pathogenesis of hypertension is modulated at least in part by vascular inflammation. We examined whether DAPK3 mediates vascular inflammatory responses and development of hypertension. In rat mesenteric arterial smooth muscle cells, small interfering RNA against DAPK3 inhibited vascular cell adhesion molecule 1 expression and monocyte adhesion induced by tumor necrosis factor-α. DAPK3 small interfering RNA inhibited phosphorylation of c-Jun amino-terminal kinase, p38, and Akt, as well as reactive oxygen species (ROS) production induced by tumor necrosis factor-α. In human umbilical vein endothelial cells, expressions of vascular cell adhesion molecule 1, endothelial selectin, and cyclooxygenase 2, as well as ROS production induced ...

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Section: October 2012supporting

confidence: 66%

Death-Associated Protein Kinase 3 Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

et al. 2012

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“…For example, it was reported that azelnidipine inhibited TNF-induced NF-κ B activation and VCAM-1 expression by the inhibition of ROS in human aortic endothelial cells (ECs) (30). Our previous study demonstrated that CV-159 inhibits TNF-induced expression of e-selectin but not VCAM-1 via suppressing the activation of JNK, p38, and NF-κ B in vascular ECs (14). We also demonstrated that CV-159 prevents activation of JNK and p38 through inhibition of ROS, while it prevents activation of NF-κ B (p65) in a ROS-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Vascular inflammatory responses represent a pathogenic feature of atherosclerosis, which is one of the major risk factors for ischemic cardiovascular disorders (10 -13). In an earlier study, we have demonstrated that CV-159 is protective against vascular endothelial inflammatory responses (14). Vascular smooth muscle cells (SMCs) proliferation and migration are also important features for the development of atherosclerosis.…”

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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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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“…Human umbilical vein endothelial cells (ECs) (HUVECs) were obtained from Kurabo (Osaka, Japan) and cultured in Medium 200 supplemented with low serum growth supplement (Cascade Biologics, Portland, OR) as described previously (39). Cells at passage from 3 to 10 were used.…”

Section: Methodsmentioning

confidence: 99%

Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation

Usui

Okada

Hara

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-α (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-κB p65 as well as reactive oxygen species (ROS) production by TNF-α. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-κB by TNF-α. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 μg·kg(-1)·day(-1)). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-α-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR.

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CV-159, a Unique Dihydropyridine Derivative, Prevents TNF-Induced Inflammatory Responses in Human Umbilical Vein Endothelial Cells

Cited by 9 publications

References 27 publications

Death-Associated Protein Kinase 3 Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

Death-Associated Protein Kinase 3 Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

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

Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation

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