Repression of phospho<i>enol</i>pyruvate carboxykinase gene activity by insulin is blocked by 3‐aminobenzamide but not by PD128763, a selective inhibitor of poly(ADP‐ribose) polymerase

Yau, Lorraine; Elliot, Tracy; Lalonde, Chantal; Zahradka, Peter

doi:10.1046/j.1432-1327.1998.2530091.x

Cited by 19 publications

(27 citation statements)

References 17 publications

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“…In addition, these data suggest that ischemic injury is not a component of the vascular repair process, as has been previously suggested (Beller et al, 2006), although induction of hypoxia-inducible factor-1␣ after angioplasty has been observed (Karshovska et al, 2007). The slight inhibition in neointimal formation obtained with 3AB was concluded to represent inhibition of ART rather than PARP, as would be expected with the concentration that was used (Yau et al, 1998).…”

Section: Discussionsupporting

confidence: 72%

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meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Yau

Molnar²,

Moon³

et al. 2008

J Pharmacol Exp Ther

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The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC 50 21 M). Treatment with 3-aminobenzamide (3AB), a less potent ART inhibitor, also produced a significant reduction in neointimal hyperplasia. Single doses (25 mM) of MIBG and 3AB were also applied within a fibrin coagulum directly to the adventitial surface of the porcine femoral artery after balloon catheter injury in vivo. MIBG reduced the neointimal index, measured 14 days after angioplasty, by 82%, whereas 3AB was ineffective. However, when extended to 45 days, the neointimal index was not significantly decreased by MIBG treatment relative to control. Assessment of MIBG release from the fibrin glue showed that the bulk of the compound was eluted within 3 days, suggesting that the vehicle was not suitable for long-term delivery. On the other hand, direct infusion of MIBG into vessels was able to reduce neointimal hyperplasia over 14 days in organ culture. These data support the conclusion that the cellular retention characteristics of MIBG contribute significantly to the efficacy of this compound. Based on these results, ART, but not PARP, may be a credible target for therapeutic treatment of restenosis.Revascularization procedures, such as balloon angioplasty, stenting, and bypass graft surgery, were developed for the treatment of coronary and peripheral arterial disease. These procedures effectively alleviate the symptoms that result from an arterial obstruction due to atherosclerosis (e.g., angina and claudication) and improve quality of life for these patients. Traditionally, the long-term efficacy of these procedures has been limited by restenosis, a reduction of the vascular lumen at the site of intervention. Restenosis rates of 20 to 50% were associated with balloon angioplasty and bare metal stents; however, the introduction of drug-eluting stents (DES) has reduced the incidence of restenosis to Ͻ10%

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Section: Discussionsupporting

confidence: 72%

“…2A), whereas the slight effect obtained with 3AB was lost at lower concentrations (Fig. 2B), specifically those that are capable of inhibiting PARP (Yau et al, 1998). The response to MIBG was concentration-dependent (EC 50 ϭ 21 M; Fig.…”

Section: Prevention Of Neointimal Hyperplasia In Vitro Bymentioning

confidence: 90%

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Yau

Molnar²,

Moon³

et al. 2008

J Pharmacol Exp Ther

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“…When 75% confluent, the growth medium was replaced with DMEM supplemented with 5 g/ml transferrin, 1 nM selenium, 20 mM ascorbate, and 10 nM insulin for 5 days. A10 SMCs and H4IIE hepatoma cells were cultured as described previously (Saward and Zahradka, 1996;Yau et al, 1998). Quiescence was achieved by placing A10 and H4IIE cells into serum-free media for 72 h, with A10 cells receiving the same supplement as the PCA-SMCs.…”

Section: Methodsmentioning

confidence: 99%

“…Quiescent cells were used for all growth assays, and PPAR agonists were added 60 min before mitogen stimulation. Specific agents used in these studies included WY14,643 (Cayman; Ann Arbor, MI), rosiglitazone [5-((4-(2-(methyl-2-pyridinylamino) (Saward and Zahradka, 1996;Yau et al, 1998). Incorporation of radiolabel into DNA was monitored by trichloroacetic acid precipitation.…”

Section: Methodsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Zahradka

Wright²,

Fuerst³

et al. 2006

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptors (PPARs) ␣ and ␥ are expressed in smooth muscle cells (SMCs). This study was designed to compare the effects of PPAR␣ and PPAR␥ on SMC proliferation and migration and to determine how they operate. Treatment of SMCs from porcine coronary artery revealed that mitogen-stimulated DNA synthesis was blocked by the PPAR␣ ligand 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643) and 15-deoxy-⌬ 12,14 prostaglandin J 2 (15d-PGJ 2 ) (a putative PPAR␥ agonist) but not by the PPAR␥ agonist rosiglitazone or the PPAR␤/␦ ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy acetic acid (GW501516). Inhibition of DNA synthesis by clofibrate and 2-(4-(2-(1-cyclohexanebutyl-3-cyclohexylureido)ethyl)phenylthio)-2-methylproprionic acid (GW7647) confirmed that SMC proliferation is affected by PPAR␣. This conclusion was supported by the fact that WY14,643 also inhibited the proliferation of H4IIE hepatoma cells (expressing only PPAR␣) but not A10 SMCs (expressing only PPAR␥1). In contrast, the effective inhibition of all cell types with 15d-PGJ 2 indicated that this compound probably operates via a PPAR␥-independent mechanism. Interestingly, rosiglitazone did not inhibit DNA synthesis of either H4IIE or A10 cells, suggesting that the activation of PPAR␥ does not influence cell proliferation. Phosphorylation of cyclin-dependent kinase 2 and expression of proliferating cell nuclear antigen were inhibited by WY14,643 but not by rosiglitazone or 15d-PGJ 2 , indicating that PPAR␣ prevents progression into S phase. Although rosiglitazone did not block SMC proliferation, it (like WY14,643) reduced neointimal hyperplasia in vitro. This observation can be rationalized by the fact that both WY14,643 and rosiglitazone inhibit SMC migration, probably through matrix metalloproteinase 9. Our study therefore shows that selective interference with mediators of cell cycle progression and cell migration via activation of PPARs may prevent growth-related vascular diseases such as restenosis and atherosclerosis.

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“…Western blotting of cellular proteins separated by SDS-PAGE in a 7.5% gel and transferred to polyvinylidene difluoride membrane was conducted as previously described (62). Horseradish peroxidase-conjugated secondary antibody (1:10,000 diluted) was detected using the ECL chemiluminescent system (Amersham).…”

Section: Methodsmentioning

confidence: 99%

Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP

Zahradka

Harding

Litchie

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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.-Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 M yielding the maximal effect. Continuous exposure for at least the first 4 -7 days of culture was essential for significant inhibition. To assess the role of matrix metalloproteinases (MMPs) in this process, we monitored MMP secretion by injured vessels in culture. Treatment with LY-294002 selectively reduced active MMP-2 in media samples according to zymography and Western blot analysis without concomitant changes in latent MMP-2. Parallel results with wortmannin indicate that MMP-2 activation is PI3K dependent. Previous research has shown a role for both furin and membrane-type 1 (MT1)-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor decanoylArg-Val-Lys-Arg-chloromethylketone did not prevent MMP-2 activation after balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY-294002. No change in MT1-MMP mRNA was observed with LY-294002, because equivalent amounts of this mRNA were present in both injured and noninjured vessels. These results implicate PI3K-dependent regulation of MT1-MMP protein synthesis and subsequent activation of latent MMP-2 as critical events in neointimal hyperplasia after vascular injury. matrix metalloproteinase; LY-294002; wortmannin; furin; restenosis PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) is a heteromeric protein consisting of an 85-kDa (p85) regulatory subunit and a 110-kDa (p110) catalytic subunit. PI3K functions as a lipid kinase and phosphorylates phosphoinositides on the 3Ј position of the inositol ring. The biological functions of PI3K can be grouped into four distinct categories: mitogenic signaling, inhibition of apoptosis, cell adherence and motility, and intracellular vesicle trafficking (5). A role in cell motility and cell adherence was indicated by evidence showing PDGF-dependent membrane ruffling and chemotaxis requires an interaction between PI3K and the PDGF receptor (25,55). In addition, PI3K is involved in microtubule reassembly in response to both insulin and PDGF (21) and actin rearrangement by PDGF (59). The involvement of PI3K in growth factor regulation of integrins and cell adherence has also been established (16,23). In particular, PI3K has been shown to associate with focal adhesion kinase (FAK) as well as participate in PDGF-mediated phosphorylation of both FAK and paxillin (40). A recent study (41) has also demonstrated that PI3K promotes cell migration on fibronectin by facilitating the binding of FAK to Src and p130Cas

show abstract

Repression of phosphoenolpyruvate carboxykinase gene activity by insulin is blocked by 3‐aminobenzamide but not by PD128763, a selective inhibitor of poly(ADP‐ribose) polymerase

Cited by 19 publications

References 17 publications

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP

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