Endothelial Vasodilator Function Is Preserved at the Spastic/Inflammatory Coronary Lesions in Pigs

Miyata, Kenji; Shimokawa, Hiroaki; Yamawaki, Tohru; Kunihiro, Ikuko; Zhou, Xiaodan; Higo, Taiki; Tanaka, Eriko; Katsumata, Naoki; Egashira, Kensuke; Takeshita, Akira

doi:10.1161/01.cir.100.13.1432

Cited by 32 publications

(34 citation statements)

References 39 publications

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“…24 Depressed production of nitric oxide seems to be another mechanism of spasm in the presence of atherosclerotic lesions, 25 even though endothelial function is preserved during vasospasm. 10,26 As for the circumferential distribution of the atherosclerotic lesions, the arc of the disease was not different between the 2 patient groups. This finding is similar to that of Tousoulis et al, 21 who demonstrated that both eccentric and concentric lesions had the same potential to induce coronary spasm, although vessel spasmogenicity may be lost in the presence of a circumferential atherosclerotic lesion.…”

Section: Advantage Of the Present Studymentioning

confidence: 90%

Plaque Morphology at Coronary Sites With Focal Spasm in Variant Angina-Study Using Intravascular Ultrasound-

Saito

Yamagishi

Takayama

et al. 2003

Circ J

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Section: Advantage Of the Present Studymentioning

confidence: 90%

Plaque Morphology at Coronary Sites With Focal Spasm in Variant Angina-Study Using Intravascular Ultrasound-

Saito

Yamagishi

Takayama

et al. 2003

Circ J

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“…We examined endothelium-dependent and -independent coronary vasomotion near the stent, as described by Miyata et al, 13 in 12 coronary arteries from 6 pigs per group. The intracoronary stent scaffolds the arterial wall and prevents vasoconstriction.…”

Section: Chronic Study: Coronary Physiology and Tissue Morphometric Amentioning

confidence: 99%

Effectiveness of Statin-Eluting Stent on Early Inflammatory Response and Neointimal Thickness in a Porcine Coronary Model

Miyauchi

Kasai

Yokayama

et al. 2008

Circ J

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irolimus-and paclitaxel-eluting stents are routinely used in coronary revascularization because drugeluting stents (DES) significantly reduce the rates of restenosis and target lesion revascularization compared with bare metal stents (BMS). 1,2 However, available DES have limitations such as stent thrombosis 3 because of local and long-term endothelial dysfunction and inflammation. 4 Late thrombosis, a life-threatening complication, has emerged as a major safety concern. Therefore, a stent-based compound that inhibits smooth muscle cell (SMC) proliferation, but does not suppress endothelial cell proliferation while restoring endothelial function, is the central goal for the development of the next generation of DES. Statins have direct anti-inflammatory properties 5 and restore endothelial function, while exerting potent antiproliferative effects upon SMCs. 6 However, the systemic administration of statins does not reduce the restenosis rate after percutaneous coronary intervention 7 and this absence of a systemic effect might be related to inadequate drug concentrations at the site of stent deployment. DES offer theoretical advantages over systemic pharmacotherapy, such as higher drug concentrations at the injury site and minimal systemic side-effects. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia. MethodsThe Animal Care and Use Committee of Juntendo University approved this study. Stainless steel balloon-expandable tubular stents (Terumo Japan Co, Tokyo, Japan; 15 mm long) were coated with a thin layer of poly-n-butyl methacrylate and polyethylene vinyl acetate copolymer, then the platform was loaded with 300 g of cerivastatin. In Vitro Drug Release KineticsThe cerivastatin-eluting stents (CES) were placed in vials containing 1 ml of 70% acetonitrile/H2O at 37°C. The cerivastatin content was measured daily using high-performance liquid chromatography (Class VP LC-10, Shimadzu Corp, Kyoto, Japan) at 238 nm for the first 14 days and then after 3 and 4 weeks to determine cerivastatin release. 8 The procedure for the control polymer stent was the same and ultraviolet absorbance values were subtracted from those of the CES. J 2008; 72: 832 -838 (Received October 11, 2007; revised manuscript received December 11, 2007; accepted December 14, 2007 Background Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stentinduced inflammatory responses and adverse effects on endothel...

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“…Recent studies have indicated that collagen accumulation and endothelial dysfunction are associated with constrictive remodeling. 34 Because endothelial vasodilator function is fairly preserved in our porcine model, 35 inflammatory vascular changes associated with collagen accumulation (especially at the adventitia) may play a primary role in the vascular remodeling.…”

Section: Rho-kinase As a Novel Therapeutic Target In Treatment Of Artmentioning

confidence: 99%

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

Morishige

Shimokawa

Eto

et al. 2001

ATVB

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Abstract-Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominantnegative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1␤, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of ␤-galactosidase, into the interleukin-1␤-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRhoK. Recent studies in vitro have suggested that the small GTP-binding protein Rho and its target protein Rho-kinase/ ROK/ROCK 2-4 play an important role in various cellular functions, including smooth muscle contraction, 5,6 actin cytoskeleton organization, 7,8 cell adhesion and motility, 9 cytokinesis, 10 and gene expression, 11 all of which may be involved in the pathogenesis of arteriosclerosis. We have recently demonstrated that Rho-kinase is functionally upregulated at the inflammatory coronary lesions and plays an important role in the pathogenesis of coronary hyperconstriction in our porcine model with interleukin (IL)-1␤. 12 The IL-1␤-treated coronary segment is characterized by luminal reduction caused by neointimal formation and constrictive remodeling. 13 Thus, our porcine model may be useful in the examination of the molecular mechanism of coronary arteriosclerosis in humans.We have recently found that hydroxyfasudil, an active metabolite of fasudil after oral absorption, is a potent and specific inhibitor of Rho-kinase and markedly inhibits coronary hyperconstriction and macrophage migration. 14,15 Thus, it is conceivable that Rho-kinase is involved not only in the pathogenesis of coronary artery spasm but also in that of coronary arteriosclerosis.To test this hypothesis, we examined in the present study whether selective inhibition of Rho-kinase by the local adenovirus-mediated transfer of dominant-negative Rhokinase (DNRhoK) can effectively induce a regression of coronary arteriosclerotic lesions in our porcine model in vivo. MethodsThis experiment was reviewed by the Committee of the Ethics on Animal Experiments at Kyushu University and was carried out under the control of the Guidelines for Animal Experiments at Kyushu University. Animal PreparationDomestic male pigs (2 to 3 months old, weighing 25 to 30 kg) were sedated with intramuscular ketamine hydrochloride...

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Endothelial Vasodilator Function Is Preserved at the Spastic/Inflammatory Coronary Lesions in Pigs

Abstract: These results indicate that endothelial vasodilator function is preserved at the spastic site and that the spasm is caused primarily by smooth muscle hypercontraction in our porcine model.

Cited by 32 publications

References 39 publications

Plaque Morphology at Coronary Sites With Focal Spasm in Variant Angina-Study Using Intravascular Ultrasound-

Plaque Morphology at Coronary Sites With Focal Spasm in Variant Angina-Study Using Intravascular Ultrasound-

Effectiveness of Statin-Eluting Stent on Early Inflammatory Response and Neointimal Thickness in a Porcine Coronary Model

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

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