Abstract 190: Continuous Vascular Remodeling Related To Development Of Arteriosclerosis Or Atherosclerosis In Kawasaki Disease ~ Immunohistochemical Study using an Animal Model ~

Background: Atherosclerotic coronary heart disease has recently emerged as a clinical issue among young individuals with a history of Kawasaki disease (KD), which is a systemic vasculitis unique to children. However, whether or not and how KD promotes atherosclerosis remains unclear. We hypothesized that, analogous to the pathogenesis of arteriosclerosis or atherosclerosis, endothelial injury and the resultant intimal thickening are induced in coronary arteries after attenuation of vasculitis. Methods: We used a rabbit model of KD developed by Onouchi et al. and performed histopathological analysis of the coronary arteries at acute (1, 3, 5, and 7 days) and chronic (3 months) phases of the disease. Results: In these rabbit models, a pan-arteritis with significant intimal cellular hypertrophy was histologically detected in the acute phase, and arterial intimal thickening was observed during the chronic phase. Immunohistochemical analysis of the coronary arteries revealed that the thickened intimal lesions observed during the chronic phase comprised abundant α-smooth muscle actin (α-SMA)-positive cells, most of which concomitantly expressed vascular cell adhesion molecule-1 and nuclear factor-κB. Although macrophages positive for RAM11 were barely detected, macrophage colony stimulating factor was strongly expressed in migrating smooth muscle cells in the intimal layer. In addition, the accumulation of proteoglycan as extracellular matrix was distinctly visible in the thickened intima, indicating progressive accumulation of lipids and proliferation of smooth muscle cells within the lesion. Conclusions: These findings suggest that, in KD-associated vasculitis, the migration of α-SMA-positive cells into the thickened intima might induce continuous vascular inflammation and remodeling, which might progress to coronary arteriosclerosis or atherosclerosis.

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A STEPWISE METHOD FOR THE ISOLATION OF ENDOTHELIAL CELLS AND SMOOTH MUSCLE CELLS FROM INDIVIDUAL CANINE CORONARY ARTERIES

In Vitro Cellular & Developmental Biology - Animal ◽

10.1290/1543-706x(2003)039<0402:asmfti>2.0.co;2 ◽

2003 ◽

Vol 39 (10) ◽

pp. 402 ◽

Cited By ~ 6

Author(s):

MICHAEL K. DAME ◽

XINWEN YU ◽

ROSARIO GARRIDO ◽

WALTER BOBROWSKI ◽

J. ERIC MCDUFFIE ◽

...

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Coronary Arteries ◽

Muscle Cells ◽

Stepwise Method

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Uptake by vascular smooth muscle cells plays an important role in targeting of lipid microspheres incorporating prostaglandin E1 into a thickened intima

Life Sciences ◽

10.1016/s0024-3205(00)00997-8 ◽

2001 ◽

Vol 68 (8) ◽

pp. 933-942 ◽

Cited By ~ 7

Author(s):

Yukihiro Chino ◽

Toshiya Minagawa ◽

Yoshiro Kohno ◽

Yoshihisa Toda ◽

Shigeru Murakami ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Prostaglandin E1 ◽

Muscle Cells ◽

Thickened Intima

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Minimally Modified LDL Upregulates Endothelin Type A Receptors in Rat Coronary Arterial Smooth Muscle Cells

Mediators of Inflammation ◽

10.1155/2013/656570 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Jie Li ◽

Lei Cao ◽

Cang-Bao Xu ◽

Jun-Jie Wang ◽

Yong-Xiao Cao

Keyword(s):

Smooth Muscle ◽

Protein Kinase C ◽

Protein Kinase ◽

Smooth Muscle Cells ◽

Coronary Arteries ◽

Muscle Cells ◽

Type A ◽

Receptor Mrna ◽

Kinase C ◽

Arterial Smooth Muscle Cells

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A () receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10 μg/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased of from control of and significantly increased receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF-κB activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the receptors in rat coronary arterial smooth muscle cells mainlyviaactivating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF-κB.

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Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00595.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. H134-H142 ◽

Cited By ~ 16

Author(s):

Praveen Shukla ◽

Srinivas Ghatta ◽

Nidhi Dubey ◽

Caleb O. Lemley ◽

Mary Lynn Johnson ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Coronary Arteries ◽

National Research Council ◽

Muscle Cells ◽

Nutrient Restriction ◽

Epoxyeicosatrienoic Acid ◽

Coronary Smooth Muscle ◽

Maternal Undernutrition ◽

Current Activation

The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in the maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control [100% U.S. National Research Council (NRC)] or nutrient-restricted (60% NRC) diet from days 50 to 130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA-resistant response to bradykinin. In fetal coronary arteries from nutrient-restricted ewes, relaxation to bradykinin was fully suppressed by NLA. Large-conductance, calcium-activated potassium channel (BKCa) currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa openers, BMS 191011 and NS1619, and 14,15-epoxyeicosatrienoic acid [a putative endothelium-derived hyperpolarizing factor (EDHF)] each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by a decreased number or activity of BKCa channels or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on nitric oxide, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.

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14,15-Dihydroxyeicosatrienoic acid relaxes bovine coronary arteries by activation of KCa channels

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00597.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. H1656-H1664 ◽

Cited By ~ 44

Author(s):

William B. Campbell ◽

Christine Deeter ◽

Kathryn M. Gauthier ◽

Richard H. Ingraham ◽

J. R. Falck ◽

...

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Coronary Arteries ◽

Epoxide Hydrolase ◽

Muscle Cells ◽

Kca Channels ◽

Vasodilator Activity ◽

Inside Out ◽

Isolated Smooth Muscle Cells

Epoxyeicosatrienoic acids (EETs) cause vascular relaxation by activating smooth muscle large conductance Ca2+-activated K+ (KCa) channels. EETs are metabolized to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. We examined the contribution of 14,15-DHET to 14,15-EET-induced relaxations and characterized its mechanism of action. 14,15-DHET relaxed U-46619-precontracted bovine coronary artery rings but was approximately fivefold less potent than 14,15-EET. The relaxations were inhibited by charybdotoxin, iberiotoxin, and increasing extracellular K+ to 20 mM. In isolated smooth muscle cells, 14,15-DHET increased an iberiotoxin-sensitive, outward K+ current and increased KCa channel activity in cell-attached patches and inside-out patches only when GTP was present. 14,15-[14C]EET methyl ester (Me) was converted to 14,15-[14C]DHET-Me, 14,15-[14C]DHET, and 14,15-[14C]EET by coronary arterial rings and endothelial cells but not by smooth muscle cells. The metabolism to 14,15-DHET was inhibited by the epoxide hydrolase inhibitors 4-phenylchalcone oxide (4-PCO) and BIRD-0826. Neither inhibitor altered relaxations to acetylcholine, whereas relaxations to 14,15-EET-Me were increased slightly by BIRD-0826 but not by 4-PCO. 14,15-DHET relaxes coronary arteries through activation of KCa channels. Endothelial cells, but not smooth muscle cells, convert EETs to DHETs, and this conversion results in a loss of vasodilator activity.

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Does Streptococcal Pyrogenic Exotoxin-C Trigger the Onset of Kawasaki Disease? -Association between Superantigens and Autoantibody against Vascular Smooth Muscle Cells-

Pediatric Research ◽

10.1203/00006450-200301000-00037 ◽

2003 ◽

Vol 53 (1) ◽

pp. 160-160

Author(s):

Hiroyuki Suzuki ◽

Yasuteru Muragaki ◽

Shigeru Uemura ◽

Takashi Takeuchi ◽

Takaomi Minami ◽

...

Keyword(s):

Smooth Muscle ◽

Kawasaki Disease ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Disease Association

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Abstract 604: Targeting Cx43 Prevents Growth Factor-Induced Phenotypic Change in Pig Coronary Artery Smooth Muscle Cells

Circulation ◽

10.1161/circ.116.suppl_16.ii_110 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Christos E Chadjichristos ◽

Sandrine Morel ◽

Jean-Paul Derouette ◽

Anne Brisset ◽

Isabelle Roth ◽

...

Keyword(s):

Smooth Muscle ◽

Coronary Artery ◽

Growth Factor ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Phenotypic Change ◽

Intimal Thickening ◽

Cx43 Expression ◽

Junction Protein ◽

Pig Coronary Artery

Percutaneous coronary intervention (PCI) is commonly used to treat atherosclerotic coronary arteries, but its efficacy is limited by restenosis at the site of the intervention. We reported previously that reducing the expression of the gap junction protein connexin43 (Cx43) in mice restricted neointima formation after acute vascular injury by limiting the inflammatory response as well as the proliferation and migration of smooth muscle cells (SMCs) towards the damaged site. SMC populations isolated from the pig coronary artery exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). S-SMCs are predominant in the normal media, whereas R-SMCs are recovered in higher proportion from stent-induced intimal thickening suggesting that they participate in the intimal thickening. Here, we further investigate the relationship between connexin expression and SMC phenotype using the distinct types of pig coronary artery SMCs. We show that Cx40 was highly expressed in normal media of porcine coronary artery in vivo, whereas Cx43 was barely detectable. In contrast, Cx40 was down-regulated and Cx43 was markedly up-regulated in SMCs of stent-induced intimal thickening. In vitro, S-SMCs expressed Cx40 and Cx43. Cx43 expression was increased in R-SMCs and these cells no longer expressed Cx40. When S-SMCs were treated with 10 ng/ml platelet-derived growth factor (PDGF-BB) they acquired a rhomboid phenotype and their migratory activity increased (from 40.3±5.7 to 185.9±27.3 migrating cells; mean±SEM, N=4, P<0.01). These changes were accompanied by an increase in Cx43 and loss of Cx40 expression. Importantly, PDGF-BB-induced phenotypic change of S-SMCs was prevented by reducing Cx43 expression with 100 uM antisense for Cx43. Thus, Cx43 antisense-treated SMCs retained their typical elongated appearance and the expression of some SMC differentiation markers, such as alpha-SM actin, whereas the appearance of S100A4, a typical marker of R-SMCs, was prevented. In conclusion, limiting Cx43 expression in SMCs prevents growth factor-induced changes towards a deleterious phenotype. Our findings suggest that Cx43 might be an additional target for local delivery strategies aimed at reducing restenosis after PCI.

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