Growth‐inhibitory effect of cyclic GMP‐ and cyclic AMP‐dependent vasodilators on rat vascular smooth muscle cells: effect on cell cycle and cyclin expression

Kronemann, Nicola; Nockher, Wolfgang Andreas; Busse, Rudi; Schini‐Kerth, Valérie B.

doi:10.1038/sj.bjp.0702305

Cited by 43 publications

(37 citation statements)

References 39 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both cGMP and over expression of its downstream kinase, cGMP-dependent protein kinase (PKG), have been shown to decrease cyclins D1, A, and E expression in vascular smooth muscle cells. [68][69][70] CNP also blocks NGF-induced increases in p27 and increases in cdk4 in response to BDNF.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Simpson

Moon²,

Kleman

et al. 2007

Cell Cycle

View full text Add to dashboard Cite

ACKnowlEdGEMEntSWe thank Amy Palmer for helpful discussions and reading of the manuscript, and Susan McTeer for manuscript preparation. This work was supported by grants NIDCD RO3 DC005704 to P.J.S., NIDCD RO1 DC02979 and NINDS RO1 NS39657 to G.V.R. AbStRACtNeuronal stem cell expansion and differentiation is a process involving stages of proliferation and maturation governed by the sequential and combinatorial exposure of cells to extrinsic factors. The olfactory epithelium is an excellent model to investigate regulation of this process, as it undergoes neuronal replacement post-natally. We have shown that the neurotrophins NGF and BDNF sequentially promote proliferation of developing olfactory sensory neuronal precursors, although their kinetics of proliferation and cell fate outcomes differ. Interestingly, CNP inhibits this neurotrophin-induced proliferation and promotes the maturation of these precursors to their next developmental stage. Here, we investigate the mechanisms behind these actions. Both NGF and BDNF increase the expression of cyclin D1 and cyclin-dependent kinase 4 (cdk4), with temporal expression patterns that parallel the proliferation kinetics of their cellular targets. The timing of cyclin D1 expression reflects differences in the need for transcription and translation in early and late stage precursors. CNP inhibits neurotrophin-induced cyclin D1 expression, and induces the expression of different profiles of inhibitory cell cycle proteins, which are neurotrophin-specific and correlate with the attainment of different maturational cell fates. Inhibition of protein degradation reverses the effects of neurotrophins and CNP on cyclin D1 and inhibitor expression levels, respectively. These results suggest a model for cell cycle regulation that involves the simultaneous expression of progressive and inhibitory cell cycle regulatory proteins in response to both proliferation and differentiation agents, followed by selective degradation of these proteins, providing a mechanism for rapid and exquisite control of the cell cycle.

show abstract

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Simpson

Moon²,

Kleman

et al. 2007

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…HuR regulates progression of the cell cycle [15][16][17] and sGC activation was shown to block progression of the cell cycle in vascular smooth muscle cells. 18 Therefore, it is conceivable that downregulation of HuR and sGC is required for hypertrophic remodeling of the aortic wall. This hypothesis is also supported by the observation that sGC is downregulated during neointima formation in rat carotid artery in response to balloon injury and that adenoviral sGC␣ 1 and sGC␤ 1 gene transfer plus NO donor application prevented neointima formation in this model.…”

Section: Significance Of Downregulation Of Hur In Chronic Hypertensionmentioning

confidence: 99%

Human-Antigen R (HuR) Expression in Hypertension

et al. 2005

View full text Add to dashboard Cite

Abstract-In aged spontaneously hypertensive rats (SHR), vasorelaxant responses to NO are attenuated compared with normotensive control rats (Wistar-Kyoto [WKY]) because of a decreased expression of the important NO receptor soluble guanylyl cyclase (sGC). Because the expression of sGC subunits ␣ 1 and ␤ 1 is controlled at the posttranscriptional level by the mRNA-binding protein human-antigen R (HuR), we now assessed whether or not altered expression of HuR could account for downregulation of sGC␣ 1 and sGC␤ 1 in genetic hypertension. The expression of HuR (and sGC␣ 1 and sGC␤ 1 ) in aortas from aged SHR was significantly decreased at the mRNA and protein level compared with age-matched WKY rats, whereas expression of HuR was not different in prehypertensive young (2 months of age) SHR and age-matched WKY rats. The mRNA-binding activity of HuR in native aortic protein extracts from aged SHR was markedly reduced compared with normotensive WKY rats, as detected by RNA electrophoretic mobility shift analysis, using biotin-labeled adenine and uracil (AU)-rich element (ARE)-containing RNA probes from the 3Ј-untranslated region of sGC␣ 1 and sGC␤ 1 . In contrast, ARE-binding activity was not different between prehypertensive young SHR and young WKY rats. In vitro RNA degradation assays using the same AU-rich sGC mRNA probes revealed an accelerated sGC␣ 1 and sGC␤ 1 mRNA decay in the presence of native protein extract from hypertensive SHR, which was less rapid with aortic protein from normotensive WKY rats. These findings suggest that in this animal model of genetic hypertension, the reduced expression of sGC subunits is mediated by downregulation of the sGC mRNA-stabilizing protein HuR. Key Words: rats, spontaneously hypertensive Ⅲ aorta Ⅲ gene regulation Ⅲ hypertension, genetic C hronic hypertension is associated with functional and morphological alterations of the vessel wall (ie, dysfunctional vascular endothelium and thickening of the smooth muscle layer). The pathomechanisms accounting for hypertension-induced vascular alterations are likely to be multifactorial. A major homeostatic factor in the vessel wall is NO, which is generated from L-arginine by endothelial NO synthase. NO reduces vascular tone by activation of soluble guanylyl cyclase (sGC) and stimulation of cGMP formation and cGMP-activated protein kinase-I (cGK-I). Activated cGK-I reduces vascular tone by interference with intracellular Ca 2ϩ mobilization 1 and inhibition of contractile filament function. 2 In animal models of hypertension such as the spontaneously hypertensive rat (SHR), disturbances of the NO-cGMP system contribute to vascular dysfunction. Thus, increased oxidative stress interfering with endogenous NO bioavailability and reduced expression of sGC interfering with NO downstream signaling have been reported. 3-5 sGC is a heterodimeric hemoprotein consisting of ␣ 1 (76 to 81.5 kDa) and ␤ 1 (70 kDa) subunits. 6 We have shown recently that the expression of sGC is subject to post-transcriptional regulation. 7 The elav-like (embryonic-le...

show abstract

“…53 cGMP, via PKG, induces MKP-1 mRNA sufficiently to inhibit growth factor-induced Erk-1/2 activity, and MKP-1 induction contributes to the antiproliferative effect of cGMP-elevating agents. 53,60 Cyclins and Cyclin Inhibitors cGMP decreases expression of cell cycle-promoting genes, such as cyclin A, D1, and E. 48,50,62 In addition, cGMP may increase expression of cell cycle inhibitors, such as p21…”

Section: Regulation Of Cell Proliferationmentioning

confidence: 99%

Regulation of Gene Expression by Cyclic GMP

Pilz

Casteel

2003

Circulation Research

260

206

View full text Add to dashboard Cite

Abstract-Cyclic GMP, produced in response to nitric oxide and natriuretic peptides, is a key regulator of vascular smooth muscle cell contractility, growth, and differentiation, and is implicated in opposing the pathophysiology of hypertension, cardiac hypertrophy, atherosclerosis, and vascular injury/restenosis. cGMP regulates gene expression both positively and negatively at transcriptional as well as at posttranscriptional levels. cGMP-regulated transcription factors include the cAMP-response element binding protein CREB, the serum response factor SRF, and the nuclear factor of activated T cells NF/AT. cGMP can regulate CREB directly, through phosphorylation by cGMP-dependent protein kinase, or indirectly, through activation of mitogen-activated protein kinase pathways; regulation of SRF and NF/AT by cGMP is indirect, through modulation of RhoA and calcineurin signaling, respectively. Downregulation of the RNA-binding protein HuR by cGMP leads to destabilization of guanylate cyclase mRNA, but this posttranscriptional mechanism may affect many more cGMP-regulated genes. In this review, we discuss the role of cGMP-regulated gene expression in (patho)physiological processes most relevant to the cardiovascular system, such as regulation of vascular tone, cardiac hypertrophy, phenotypic modulation of vascular smooth muscle cells, and regulation of cell proliferation and apoptosis.

show abstract

Growth‐inhibitory effect of cyclic GMP‐ and cyclic AMP‐dependent vasodilators on rat vascular smooth muscle cells: effect on cell cycle and cyclin expression

Cited by 43 publications

References 39 publications

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Human-Antigen R (HuR) Expression in Hypertension

Regulation of Gene Expression by Cyclic GMP

Contact Info

Product

Resources

About