Vasodilator-Stimulated Phosphoprotein Regulates Cell Proliferation and Growth Inhibition by Nitric Oxide in Vascular Smooth Muscle Cells

Chen, Lihua; Daum, Günter; Chitaley, Kanchan; Coats, Scott A.; Bowen‐Pope, Daniel F.; Eigenthaler, Martin; Thumati, Naresh R.; Walter, Ulrich; Clowes, A. W.

doi:10.1016/j.carpath.2004.03.125

Cited by 5 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VASP is phosphorylated by protein kinase C, cAMP kinase, and cGKI at two sites with different preference. Recently, it was reported that expression of VASP and phosphorylation of Ser-157 increased proliferation whereas phosphorylation of Ser-239 decreased proliferation (49). Surprisingly, serum as used in cell culture studies stimulates phosphorylation of Ser-157 of VASP through PKC (50), an effect of serum not noticed so far.…”

mentioning

confidence: 96%

The Biology of Cyclic GMP-dependent Protein Kinases

Hofmann

2005

Journal of Biological Chemistry

223

192

View full text Add to dashboard Cite

Basic Properties of cGMP-dependentProtein Kinase Isoforms cGKs 1 belong to the family of serine/threonine kinases and are present in a variety of eukaryotes ranging from the unicellular organism Paramecium to Homo sapiens (1, 2). Mammals have two cGK genes, prkg1 and prkg2, that encode cGKI and cGKII. The N terminus (the first 90 -100 residues) of cGKI is encoded by two alternatively spliced exons that produce the isoforms cGKI␣ and cGKI␤. The enzymes have a rod-like structure and are activated at submicromolar to micromolar concentrations of cGMP (3, 4). They are composed of three functional domains: an N-terminal (A) domain, a regulatory (R) domain, and a catalytic (C) domain (for details see Refs. 1 and 2). The regulatory domain contains two tandem cGMP-binding sites that interact allosterically and bind cGMP with high and low affinity. Occupation of both binding sites induces a large change in secondary structure (5) to yield a more elongated molecule (6, 7). The catalytic domain contains the MgATP-and peptide-binding pockets. Binding of cGMP to both sites in the R domain releases the inhibition of the catalytic center by the N-terminal autoinhibitory/pseudosubstrate site and allows the phosphorylation of serine/threonine residues in target proteins and in the N-terminal autophosphorylation site. Activation of heterophosphorylation may be preceded by autophosphorylation. Autophosphorylation increases the spontaneous activity of cGKI and cGKII (8 -11) and is initiated by the binding of low cGMP concentrations to the high affinity site of cGKI (12,13). In addition to controlling activation and inhibition of the catalytic center, the N terminus has two other functions: dimerization, cGKs are homodimers that are held together by a leucine zipper present in the N terminus, and targeting, the enzymes are targeted to different subcellular localizations by their N termini.Tissue Distribution cGKI is present in high concentrations (Ͼ0.1 M) in all smooth muscles, platelets, cerebellum, hippocampus, dorsal root ganglia, neuromuscular endplate, and kidney. Low levels have been identified in cardiac muscle, vascular endothelium, granulocytes, chondrocytes, and osteoclasts. The I␣ isozyme is found in lung, heart, dorsal root ganglia, and cerebellum. Together with the I␣ isozyme, the I␤ isozyme is highly expressed in smooth muscle, including uterus, vessels, intestine, and trachea (14). Platelets, hippocampal neurons, and olfactory bulb neurons contain mainly the I␤ isozyme (14). The I␣ and I␤ cGKs are soluble enzymes and interact with different proteins through their distinct N termini. cGKII is expressed in several brain nuclei, intestinal mucosa, kidney, adrenal cortex, chondrocytes, and lung (15)(16)(17)(18). cGKII is anchored at the plasma membrane by myristoylation of the N-terminal Gly-2 residue. Only the membrane-bound cGKII phosphorylates cystic fibrosis transmembrane conductance regulator (19). Roles of cGKIControl of Smooth Muscle Tone by cGKI-NO and other NOgenerating organic nitrates stimulate the soluble gua...

show abstract

mentioning

confidence: 96%

The Biology of Cyclic GMP-dependent Protein Kinases

Hofmann

2005

Journal of Biological Chemistry

223

192

View full text Add to dashboard Cite

show abstract

“…In the vascular wall, phosphorylation of VASP at Ser-239 (24) (product denoted P Ser-239 -VASP) is regulated by NO and prostacyclin. Phosphorylation of VASP at Ser-239 is a sensitive monitor of defective vascular NO͞cGMP signaling (25,26), endothelial dysfunction (27,28), and vascular oxidative stress (29).…”

mentioning

confidence: 99%

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Melichar¹

2004

Proceedings of the National Academy of Sciences

View full text Add to dashboard Cite

Atherosclerosis is associated with alterations in nitric oxide (NO)͞ cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein (p38 nt ) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO͞cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential downregulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.hypercholesterolemia ͉ soluble guanylyl cyclase ͉ vasodilator-stimulated phosphoprotein ͉ cGMP-dependent protein kinase A therosclerosis is major risk factor to cardiovascular diseases such as coronary heart disease and stroke. The pathophysiology of atherosclerosis is highly complex, multifactorial, and yet to be fully understood (1). A common feature observed is malperfusion of tissues as a result of luminally obstructive atherosclerotic plaques, augmented vascular tone, and reduced sensitivity to endothelium-dependent vasodilators in atherosclerotic arteries from humans (2) and cholesterol-fed animals (3).Nitric oxide (NO) is an important antiatherosclerotic autocoid, which exerts antiproliferative and vasodilatory effect on vasculature and antiaggregatory effect on platelets. Vascular dysfunction in atherosclerosis is partly attributed to reduced tetrahydrobiopterin-dependent (4-7) production or bioavailability of endothelium-derived NO (8), which is supported by the observation of reduced activity and expression of endothelial NO synthase III (NOS-III) (9) in atherosclerotic vessels (10, 11). Additionally, the tissue half-life of NO is further reduced by reactive oxygen species (superoxide, O 2 Ϫ ) that scavenge NO and thereby impair its vasoprotective activity (12). Therefore, formation of O 2 Ϫ , by NADPH oxidase (13, 14) or xanthine oxidase (15) or uncoupled endothelial NOS (16) and͞or its decomposition, by superoxide dismutase (SOD) (17)(18)(19), are thought to play important roles in the pathogenesis of atherosclerosis.Endothelium-derived NO stimulates the production of the se...

show abstract

“…In vascular endothelial cells, overexpression of VASP has been shown to induce stress fiber formation and membrane ruffling (20). VASP activity is regulated through phosphorylation by cAMPdependent protein kinases (PKA) and PKG at distinct sites (21)(22)(23)(24). Phosphorylation of VASP may affect its capacity to associate with actin filaments and antagonize filament branching (25,26).…”

mentioning

confidence: 99%

Atrial Natriuretic Peptide-initiated cGMP Pathways Regulate Vasodilator-stimulated Phosphoprotein Phosphorylation and Angiogenesis in Vascular Endothelium

Chen

Levine

Golan

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

cGMP is involved in numerous vascular signaling pathways, and abnormalities in these pathways have been implicated in the pathophysiology of hypertension, atherosclerosis, and diabetes (1, 2). In endothelial cells, cGMP is synthesized by two distinct guanylate cyclase (GC) 5 isoforms, the nitric oxide (NO)-activated soluble GC (sGC) and the atrial natriuretic peptide (ANP)-activated particulate GC (GC-A) (2-4). NO, produced by endothelial NO synthase (eNOS), plays a crucial role in a variety of vascular responses such as blood pressure control, platelet aggregation, and vascular smooth muscle cell proliferation (5). Activation of eNOS is strongly influenced by a diverse collection of cell surface receptors, including vascular endothelial growth factor (VEGF) receptor (KDR) and sphingosine 1-phosphate (S1P) receptor S1P 1 (Edg-1) (6, 7). ANP is released primarily by cardiac atria in response to atrial stretch; this peptide binds with high affinity to the membrane receptor guanylate cyclase GC-A located in renal cells and in the vasculature (8, 9). Activated GC-A promotes diuresis and inhibits the renin-angiotensin-aldosterone system, thereby controlling salt and water retention and blood pressure (10). Recent studies have revealed ANP to be an endogenous vasoprotective substance as well as a potent pharmacological agent in the treatment of cardiovascular diseases (10 -12). GC-A is abundantly expressed in the vascular endothelium, and binding of ANP to GC-A significantly increases intracellular cGMP levels (13-15).The principal effectors of cGMP in the cardiovascular system include cGMP-gated monovalent cation channels, phosphodiesterases, and cGMP-dependent protein kinases (PKGs) (16,17). Two mammalian PKG genes have been identified, encoding PKG I and PKG II. PKG I is the prevalent PKG isoform expressed in the cardiovascular system (17) and will be referred to here as PKG. Although the functions of PKG have been probed both with PKG knock-out mice and with analyses of cellular substrates phosphorylated by PKG, much remains to be understood about the molecular and cellular significance of PKG signaling in endothelial homeostasis. PKG knock-out mice display decreased life span, impaired vascular smooth * This work was supported in part by Grants HL46457, HL48743, GM36259 (to T. M.), HL32854, and HL70819 (to D. E. G.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

show abstract

Vasodilator-Stimulated Phosphoprotein Regulates Cell Proliferation and Growth Inhibition by Nitric Oxide in Vascular Smooth Muscle Cells

Cited by 5 publications

References 0 publications

The Biology of Cyclic GMP-dependent Protein Kinases

The Biology of Cyclic GMP-dependent Protein Kinases

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Atrial Natriuretic Peptide-initiated cGMP Pathways Regulate Vasodilator-stimulated Phosphoprotein Phosphorylation and Angiogenesis in Vascular Endothelium

Contact Info

Product

Resources

About