Inhibition of Intimal Thickening in the Rat Carotid Artery Injury Model by a Nontoxic Ras Inhibitor

George, Jacob; Sack, Jessica; Barshack, Iris; Keren, Pnina; Goldberg, Iris; Haklai, Roni; Elad-Sfadia, Galit; Kloog, Yoel; Keren, Gad

doi:10.1161/01.atv.0000112021.98971.f0

Cited by 23 publications

(24 citation statements)

References 30 publications

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“…48 Likewise, the MAPK pathway is activated by balloon-induced stretch in coronary and carotid arteries, 49 and neointimal hyperplasia in a rat carotid artery injury model was attenuated by administration of a farnesyltransferase inhibitor that effectively downregulates Ras activity. 50 It is important to establish the specific activity of neurofibromin that is responsible for vascular disease in NF1, and our results demonstrate that it is the Ras-GAP function of the protein that is critical, at least in this mouse model. Furthermore, our data that implicate activation of the S6K/mTOR pathway in injured Nf1-deficient arteries are consistent with recent reports of mTOR activation downstream of Ras in other NF1 models 31,32 and with a large body of work that confirms the vital role of this pathway in vascular restenosis.…”

Section: Discussionmentioning

confidence: 68%

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

Ismat

Wang

et al. 2007

Circulation

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Background-Neurofibromatosis type I (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, osseous dysplasias, and characteristic cutaneous findings. In addition, NF1 patients have an increased incidence of cardiovascular diseases, including obstructive vascular disorders. In animal models, endothelial expression of the disease gene, NF1, is critical for normal heart development. However, the pathogeneses of the more common vascular disorders are not well characterized. Methods and Results-To examine the role of NF1 in vascular smooth muscle, we generated mice with homozygous loss of the murine homolog Nf1 in smooth muscle (Nf1smKO). These mice develop and breed normally. However, in response to vascular injury, they display a marked intimal hyperproliferation and abnormal activation of mitogenactivated protein kinase, a downstream effector of Ras. Vascular smooth muscle cells cultured from these mice also display enhanced proliferation and mitogen-activated protein kinase activity. Smooth muscle expression of the NF1 Ras-regulatory domain (GTPase activating protein-related domain) rescues intimal hyperplasia in Nf1smKO mice and normalizes vascular smooth muscle cell Ras effector activity and proliferation in vitro, similar to blockade of downstream effectors of Ras. Conclusions-In this in vivo model of NF1 obstructive vascular disease, we have shown that Nf1 regulation of Ras plays a critical role in vascular smooth muscle proliferation after injury. These results suggest opportunities for targeted therapeutics in the prevention and treatment of NF1-related vascular disease and in the treatment of neointimal proliferation in other settings.

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Section: Discussionmentioning

confidence: 68%

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

Ismat

Wang

et al. 2007

Circulation

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“…Salirasib (FTS) was found to inhibit intimal thickening in rat carotid artery injury model. 59 FTS inhibited VSMC and splenocytes proliferation, reduced the levels of active Ras and active ERK in balloon injured rat arteries, and reduced the number of NFkB-and iNOS-positive cells in sections of the injured arteries. 59 Salirasib went through phase I clinical trials with no reported adverse side effects.…”

Section: Tyrphostin (Agl-2043)mentioning

confidence: 85%

“…59 FTS inhibited VSMC and splenocytes proliferation, reduced the levels of active Ras and active ERK in balloon injured rat arteries, and reduced the number of NFkB-and iNOS-positive cells in sections of the injured arteries. 59 Salirasib went through phase I clinical trials with no reported adverse side effects. The hydrophobic nature of FTS, which also contains a hydrophilic carboxyl group, may suggest that it could be an appropriate drug for stents.…”

Section: Tyrphostin (Agl-2043)mentioning

confidence: 85%

Approaches for prevention of restenosis

2007

Self Cite

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Coronary artery disease is characterized by a narrowing (stenosis) of the arteries that supply blood to the tissue of the heart. Continued restriction of blood flow manifests itself as angina and ultimately myocardial infarction (heart attack) for the patient. Heart bypass was once the only treatment for this condition, but over the years percutaneous coronary intervention (PCI) has become an increasingly attractive alternative to medical therapy and surgical revascularization for the treatment of coronary artery disease. A vascular stent is a medical device designed to serve as a temporary or permanent internal scaffold, to maintain or increase the lumen of a blood vessel. Metallic coronary stents were first introduced to prevent arterial dissections and to eliminate vessel recoil and intimal hyperplasia associated with PCI. Further advancement in the treatment of coronary artery disease is the development of drug-eluting stents that dramatically reduce the incidence of in-stent restenosis to less than 5%. Local drug delivery offers the advantages of allowing a relatively high local concentration of drug at the treatment site while minimizing systemic toxic effect. This review describes approaches for prevention of restenosis. It focuses on drugs for prevention of restenosis, bare metal stents, and drug-eluting stents. It also describes recent advances in bioresorbable stents. One of the chapters is dedicated to our novel composite bioresorbable drug-eluting fibers, designed to be used as basic elements in drug-eluting stents.

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“…Ras activation because of oxidative stress and H-Ras minisatellite instability in atherosclerotic plaque indicated that increased Ras activity may be involved in atherosclerosis (71). Ras inhibition using farnesyltransferase inhibitors attenuated atherosclerotic lesion formation and reduced oxidative stress in apoE-deficient mice (71,72) and intimal thickening in the rat carotid injury model (73). Statins, which interfere with Ras prenylation and activity, reduce angiogenesis and plaque progression (74).…”

Section: Discussionmentioning

confidence: 99%

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

Wood

Mulay

Darabi

et al. 2011

Journal of Biological Chemistry

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The mitogen-activated protein kinase (MAPK) Erk1/2 has been implicated to modulate the activity of nuclear receptors, including peroxisome proliferator activator receptors (PPARs) and liver X receptor, to alter the ability of cells to export cholesterol. Here, we investigated if the Ras-Raf-Mek-Erk1/2 signaling cascade could affect reverse cholesterol transport via modulation of scavenger receptor class BI (SR-BI) levels. We demonstrate that in Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells, Mek1/2 inhibition reduces PPAR␣-inducible SR-BI protein expression and activity, as judged by reduced efflux onto high density lipoprotein (HDL). Ectopic expression of constitutively active H-Ras and Mek1 increases SR-BI protein levels, which correlates with elevated PPAR␣ Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPAR␣-depleted cells. Most strikingly, Mek1/2 inhibition promotes SR-BI degradation in SR-BI-overexpressing CHO cells and human HuH7 hepatocytes, which is associated with reduced uptake of radiolabeled and 1,1 -dioctadecyl-3,3,3 ,3 -tetramethylindocarbocyane-labeled HDL. Loss of Mek1/2 kinase activity reduces SR-BI expression in the presence of bafilomycin, an inhibitor of lysosomal degradation, indicating down-regulation of SR-BI via proteasomal pathways. In conclusion, Mek1/2 inhibition enhances the PPAR␣-dependent degradation of SR-BI in hepatocytes.Anti-atherosclerotic properties of HDL and the major HDL apolipoprotein, apoA-I, are believed to include their ability to induce signaling events that promote cholesterol export from peripheral cells to the liver for disposal. However, the signal transduction pathways that contribute to stimulate reverse cholesterol transport in macrophages and hepatocytes are not fully understood (1-3). HDL binding to receptors such as SR-BI 6 activates various cellular processes, including endothelial nitric-oxide synthase activation in endothelial cells (1-3) and proliferation in smooth muscle cells (4) but also cell surface localization of SR-BI in hepatocytes (5). Downstream targets of HDL include Src family kinases, phospholipase C and D, Ras, phosphatidylinositol 3-kinase (PI3K), Akt, the mitogen-activated protein kinase (MAPK) pathway (Mek1/2 and Erk1/2), and Rac/Rho GTPases (1-8). Other kinases implicated in HDL-or apoAI-inducible cholesterol transport include protein kinase C (PKC), protein kinase A (PKA), c-Jun N-terminal kinase (JNK), and p38 MAPK (9 -14).Alternatively, signaling pathways can modulate the activity of nuclear receptors, including PPAR and LXR, to alter the ability of cells to transport cholesterol (15-18). Indeed, post-translational phosphorylation via various kinases, including Erk1/2, can alter PPAR␣ and PPAR␣ co-activator activity in a liganddependent and -independent manner (17-25). Recent findings link Erk1/2 kinases with nuclear receptors and lipid export via ABCA1. First, enhanced Erk1/2 signaling increases ABCA1 expression and ABCA1-mediated phos...

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Inhibition of Intimal Thickening in the Rat Carotid Artery Injury Model by a Nontoxic Ras Inhibitor

Cited by 23 publications

References 30 publications

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response

Approaches for prevention of restenosis

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

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