Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation

Koyama, Hideki; Bornfeldt, Karin E.; Fukumoto, Shinya; Nishizawà, Yoshiki

doi:10.1002/1097-4652(200101)186:1<1::aid-jcp1012>3.0.co;2-d

Cited by 79 publications

(9 citation statements)

References 116 publications

(145 reference statements)

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“…The expression of B-Raf in cells is therefore thought to determine whether cyclic AMP will activate (Rap1) or inhibit (PKA) ERK signaling (5,27,35,39). In previous analyses of VSMCs, cyclic AMP was reported to reduce signaling through the Raf/MEK/ERK pathway (21,23,30). This likely reflects a low expression of B-Raf (24) and a predominance of a PKA-dependent inhib- Fig.…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors

Eid¹,

Chotani²,

Mitra³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Cold increases cutaneous vasoconstriction by unmasking the contractile activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) in vascular smooth muscle cells (VSMCs), which is mediated by the cold-induced mobilization of alpha(2C)-ARs from the transGolgi to the cell surface. The expression of alpha(2C)-ARs in human cutaneous VSMCs is under dual regulation by cyclic AMP: gene transcription is inhibited by cyclic AMP acting through protein kinase A but is increased by cyclic AMP acting through the exchange protein directly activated by cyclic AMP (EPAC) and the GTP-binding protein Rap1. Experiments were performed to further characterize the Rap1 signaling pathway. Forskolin (10 muM), the selective EPAC activator, 8-pCPT-2'-O-Me-cyclic AMP (CMC; 100 microM), or a constitutively active mutant of Rap1 (Rap1CA) increased the activity of c-Jun NH(2)-terminal kinase (JNK) in human cutaneous VSMCs. This was associated with the increased phosphorylation of c-Jun and activation of an activator protein (AP)-1 reporter construct, which were inhibited by the JNK inhibitor SP600125 (3 microM). Rap1CA increased the activity of an alpha(2C)-AR promoter-reporter construct, which was inhibited by SP600125 (3 microM) or by the mutation of an AP-1 binding site in the alpha(2C)-AR promoter. Furthermore, forskolin (10 microM) or CMC (100 microM) increased the expression of the alpha(2C)-AR protein, and these effects were inhibited by SP600125 (3 microM). Therefore, cyclic AMP increases the expression of alpha(2C)-ARs in cutaneous VSMCs by activating a novel Rap1 signaling pathway, mediated by the activation of JNK, AP-1, and the subsequent transcriptional activation of the alpha(2C)-AR gene. By increasing the expression of cold-responsive alpha(2C)-ARs, this pathway may contribute to enhanced cold-induced vasoconstriction in the cutaneous circulation, including Raynaud's phenomenon.

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Section: Discussionmentioning

confidence: 99%

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors

Eid¹,

Chotani²,

Mitra³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Endothelial derived relaxing factors, such as NO or prostacyclin (PGI2), relax blood vessels and inhibit the proliferation and migration of SMCs by increasing synthesis of the cyclic nucleotides cAMP or cGMP. In fact, cAMP and cGMP inhibit the proliferation of arterial SMCs [111], and elevation of cyclic nucleotides reduces neointimal formation after angioplasty in animal models. Oral administration for 3-21 days of milrinone (0.3-3.0 mg/kg), a bipyridine derivative that specifically inhibits PDE3, suppressed intimal thickening by up to 56% in a dose-and time-dependent manner in a mouse model of photochemically induced vascular injury [112].…”

Section: Vascular Diseasementioning

confidence: 99%

Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Jeon

Heo

Kim

et al. 2005

CMLS, Cell. Mol. Life Sci.

225

174

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Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.

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“…These signals regulate numerous fundamental biological processes, including gene expression, cell proliferation and differentiation, cellular migration, and apoptosis. 1,2 Cyclic nucleotides exert both pro-and anti-apoptotic actions depending on the cell type. Some investigators have reported that cAMP and cGMP analogs cause apoptosis, e.g.…”

Section: Introductionmentioning

confidence: 99%

Cyclic AMP and Cyclic GMP suppress TNFα-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway

et al. 2006

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Cyclic AMP (cAMP) and cyclic GMP (cGMP) suppress apoptosis in many cell types, including hepatocytes. We have previously shown that membrane-permeable cAMP and cGMP analogs attenuate tumor necrosis factor alpha plus actinomycin D (TNFalpha/ActD)-induced apoptosis in hepatocytes at a step upstream of caspase activation and cytochrome c release. Recently we have also shown that FADD levels increase 10 folds in response to TNFalpha/ActD. Therefore we hypothesized that cAMP and cGMP would inhibit FADD upregulation. We show here that cyclic nucleotide analogs dibutyryl cAMP (db-cAMP) and 8-bromo-cGMP (Br-cGMP) inhibit cell death and the cleavages of multiple caspases including caspase-10, -9, -8, -3, and -2, as well as suppress FADD protein up-regulation in TNFalpha/ActD-induced apoptosis. The inhibitory effects of cAMP were seen at lower concentrations than cGMP. Both cAMP and cGMP prevented FADD overexpression and cell death in hepatocytes transfected with the FADD gene. A protein kinase A (PKA) inhibitor, KT 5720, reversed the inhibition of FADD protein levels induced by cAMP or cGMP. In conclusion, our findings indicate that cAMP and cGMP prevent TNFalpha/ActD-induced apoptosis in hepatocytes and that this occurs in association with a near complete inhibition of the upregulation of FADD via a PKA-dependent mechanism.

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Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation

Cited by 79 publications

References 116 publications

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors

Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Cyclic AMP and Cyclic GMP suppress TNFα-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway

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Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation

Cited by 79 publications

References 116 publications

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α2C-adrenoceptors

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α2C-adrenoceptors

Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Cyclic AMP and Cyclic GMP suppress TNFα-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway

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Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle α_2C-adrenoceptors