Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys

Ohtani, Kisho; Usui, Makoto; Nakano, K.; Kohjimoto, Yoshiro; Kitajima, Shun Ichi; Hirouchi, Yasuhiko; Li, X. H.; Kitamoto, Shiro; Takeshita, Akira; Egashira, Kensuke

doi:10.1038/sj.gt.3302288

Cited by 48 publications

(51 citation statements)

References 32 publications

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“…The higher CS incidence in the C-carriers is in line with the role of MCP-1 in atherogenesis, restenosis, and plaque destabilization (42)(43)(44) as well as with the fact that patients with stroke or cardiovascular diseases show elevated MCP-1 plasma levels (45,46). The increased platelet count and high fibrinogen concentrations that we found in C-subjects fit the known association of these factors with severe CS and risk of stroke (47,48).…”

Section: Discussionsupporting

confidence: 71%

The +838 C/G MT2A Polymorphism, Metals, and the Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People

Giacconi

Muti

Malavolta

et al. 2007

Mol Med

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Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity. A recent investigation of older patients with diabetes and atherosclerosis showed an association between the -209 A/G MT2A polymorphism, CS, and zinc status. In this study, we evaluated the relationship between two MT2A polymorphisms (-209 and + 838 locus), metal status, and inflammatory/immune response in older patients with CS only (the CS1 group) or with CS and previous cerebrovascular episodes (transient ischemic attack or stroke) (the CS2 group). A total of 506 individuals (188 CS1, 100 CS2, and 218 healthy controls) were studied. Atherosclerotic patients (CS1 and CS2) showed increased levels of MT, MCP-1, and RANTES, reduced NK cell cytotoxicity, and altered trace element concentrations (zinc, copper, magnesium, iron). The +838 C/G MT2A polymorphism was differently distributed in CS1 and CS2 patients, who displayed the GG genotype (C-) with significantly higher frequency than elderly controls. C-carriers showed increased MCP-1 and decreased NK cell cytotoxicity, CD56+ cells, and intracellular zinc availability along with decreased zinc, copper, and magnesium content in erythrocytes and increased iron in plasma. C-carriers also showed a major incidence of soft carotid plaques. In conclusion, the +838 C/G MT2A polymorphism seems to influence inflammatory markers, zinc availability, NK cell cytotoxicity, and trace element status, all of which may promote CS development.

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Section: Discussionsupporting

confidence: 71%

The +838 C/G MT2A Polymorphism, Metals, and the Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People

Giacconi

Muti

Malavolta

et al. 2007

Mol Med

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“…As we reported previously, 15 inflammatory changes and apoptotic cell death became evident 7 to 10 days after stent implantation in rabbits (Figure 2a and 2b). Treatment with olmesartan reduced such inflammatory changes and enhanced cell death in the intima after stenting.…”

Section: Inhibitory Effects Of Arb On Inflammatory Changes and Apoptosupporting

confidence: 61%

“…To gain clinical significance for the results, we used a nonhuman primate model of in-stent neointima formation. 15 We then aimed to investigate the underlying mechanism in a rabbit model. We demonstrate that: (1) increases in local expression of RAS begin at early stages after stenting, and (2) treatment with ARB attenuates in-stent neointima formation associated with reduction in oxidative stress, inflammatory changes, and AT 1 receptor expression.…”

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confidence: 99%

Angiotensin II Type 1 Receptor Blockade Attenuates In-Stent Restenosis by Inhibiting Inflammation and Progenitor Cells

et al. 2006

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Abstract-The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by Ϸ30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Key Words: angiotensin II Ⅲ oxidative stress Ⅲ monocytes C oronary intervention with metal stent implantation is performed in Ͼ1.5 million patients with atherothrombotic lesions worldwide and has become the major revascularization technique. 1 The clinical benefits of this procedure are reduced by in-stent restenosis. In-stent restenosis results exclusively from neointima formation because of proliferation/migration of smooth muscle cells and inflammatory changes in response to stent-associated injury. 2 Recent clinical trials demonstrated great benefits of drug-eluting stents (containing sirolimus, paclitaxel, etc) in preventing restenosis and improving clinical outcomes. 3,4 However, systemic medical therapies for stentassociated thrombosis and for control of risk factors are essential therapy in addition to drug-eluting stents for the prevention of future coronary events. This notion is supported by recent reports showing multiple atherosclerotic plaque ruptures at sites other than the culprit lesion, as observed in acute coronary syndrome by intravascular ultrasound analysis. 5 The renin-angiotensin system (RAS) has been implicated in the pathogenesis of restenosis and acute coronary syndrome 6 -11 and, thus, may be a potential target for the prevention of in-stent restenosis and atherothrombotic events. Indeed, a recent, single-center VALsartan for Prevention of REstenosis after Stenting of Type B2/C lesions (Val-PREST) trial demonstrated that treatment with angiotensin II type 1 (AT 1 ) receptor blocker (ARB) reduces the incidence of restenosis and revascularization in selected patients with type B2/C lesions. 12 The same group compared valsartan with angiotensin-converting enzyme (ACE) inhibition after bare metal stent implantation in the VALsartan Versus ACE inhibition (VALVACE) trial and reported greater benefits from systemic valsartan treatment than from angiotensinconverting enzyme inhibitors in reducing r...

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“…The left coronary artery was perfused with 10% buffered formalin at 120 mmHg and fixed for 24 hours. The stented artery segments were isolated and processed as described previously 26) . The segment was divided into two parts at the center of the stent and then embedded in methyl methacrylate mixed with n-butyl methacrylate to allow for sectioning through the metal stent struts.…”

Section: Histopathological Studymentioning

confidence: 99%

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

Tsukie

Nakano

Matoba

et al. 2013

JAT

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Aim:The use of currently marketed drug-eluting stents presents safety concerns including increased late thrombosis, which is thought to result mainly from delayed endothelial healing effects (impaired re-endothelialization resulting in abnormal inflammation and fibrin deposition). We recently developed a bioabsorbable polymeric nanoparticle (NP)-eluting stent using a novel cationic electrodeposition technology. Statins are known to inhibit the proliferation of vascular smooth muscle cells (VSMC) and to promote vascular healing. We therefore hypothesized that statin-incorporated NPeluting stents would attenuate in-stent stenosis without delayed endothelial healing effects. Methods: Among six marketed statins, pitavastatin (Pitava) was found to have the most potent effects on VSMC proliferation and endothelial regeneration in vitro. We thus formulated a Pitava-NP-eluting stent (20 μg Pitava per stent). Results: In a pig coronary artery model, Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as polymer-coated sirolimus-eluting stents (SES). At SES sites, delayed endothelial healing effects were noted, whereas no such effects were observed in Pitava-NP-eluting stent sites. Conclusion: Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as SES without the delayed endothelial healing effects of SES in a porcine coronary artery model. This nanotechnology platform could be developed into a safer and more effective device in the future.

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Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys

Cited by 48 publications

References 32 publications

The +838 C/G MT2A Polymorphism, Metals, and the Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People

The +838 C/G MT2A Polymorphism, Metals, and the Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People

Angiotensin II Type 1 Receptor Blockade Attenuates In-Stent Restenosis by Inhibiting Inflammation and Progenitor Cells

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

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