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Biomedical subjects

H M Kwon

Publications and source records attributed to H M Kwon.

At least 55 records · Page 3Linked to original sources
PubMed1998

Experimental hypercholesterolemia induces ultrastructural changes in the internal elastic lamina of porcine coronary arteries.

The internal elastic lamina (IEL) serves as a barrier for cells and macromolecules migration between the intima and the media in the vascular wall. Several investigators have reported internal elastic lamina ultrastructural changes in elastic arteries with atherosclerosis. However, no quantitative and qualitative assessment of the internal elastic lamina architecture in muscular arteries such as the coronary circulation during early atherosclerosis have been performed yet. In this study, we therefore evaluated the ultrastructural morphological changes of the IEL in the coronary circulation of pigs fed with high cholesterol diet. Animals were sacrificed after being fed either a high cholesterol diet for 10-12 weeks (n = 5, 12 coronary segments) or a control diet (n = 4, 15 coronary segments). Coronary arteries were analyzed by transmission and scanning electron microscopy. In addition, computerized digital analysis of the images obtained by confocal scanning microscopy was performed for the quantitation of the morphologic changes in the internal elastic lamina. Confocal microscopy and scanning electron microscopy revealed an altered pattern characterized by large oval fenestration formation in the internal elastic lamina of hypercholesterolemic animals. Computerized morphometric analysis of confocal microscopy images demonstrated that compared to controls, the IEL of cholesterol-fed animals was characterized by an increase in the minor diameter of the fenestrae (2.16 +/- 0.04 microm versus 3.32 +/- 0.06 microm, P = 0.003) and a decrease in the fenestrae density (22333 +/- 1334/mm2 versus 17552 +/- 931/mm2, P = 0.015) of the internal elastic lamina. The percentage of the IEL area covered by the fenestrae correlated with the intimal thickness (r = 0.79, P = 0.004). This study demonstrates that experimental hypercholesterolemia is characterized by ultrastructural changes of the internal elastic lamina in the coronary circulation. This study suggests that the IEL may play an important role in the development of structural changes which characterize the early phase of coronary atherosclerosis.

Animals↗
PubMed1998

Fibrin-film stenting in a porcine coronary injury model: efficacy and safety compared with uncoated stents.

OBJECTIVES: This study was designed to test the efficacy and safety of a fibrin-film-covered stent compared with that of a bare metal stent in the porcine coronary injury model. BACKGROUND: Biodegradable stents are a potential method of achieving total lesion coverage and delivering local, lesion-specific drug therapy. METHODS: Two coronary arteries in each pig were randomly assigned to deployment of either a fibrin-film or a bare tantalum wire-coil stent. An oversized balloon injury, 1.15 to 1.30 times the reference vessel diameter, was induced in each coronary segment before stenting to simulate angioplasty injury. Thirty pigs were studied: group 1 for 28 days (15 pigs); group 2 for 90 days (5 pigs); group 3 for 6 months (5 pigs); group 4 for 1 year (5 pigs). RESULTS: Two pigs died of occlusion of the bare stent and one of occlusion of the fibrin stent (p > 0.99). There were no significant differences between the fibrin-stented and bare-stented coronary segments with regard to arterial injury. In group 1 (28 days, 14 pigs), the mean neointimal thicknesses in the fibrin-stented and bare-stented groups were 0.57+/-0.31 and 0.57+/-0.27 mm, respectively (p=0.89). In groups 2 to 4 (90 days, four pigs; 6 months, four pigs; 1 year, five pigs), the mean neointimal thicknesses for fibrin- and bare-stented coronary segments at the times studied were 0.48+/-0.26 versus 0.50+/-0.22 mm at 90 days; 035+/-0.04 versus 0.35+/-0.16 mm at 6 months; and 0.33+/-0.14 versus 0.30+/-0.14 mm at 1 year (p=0.98). CONCLUSIONS: Fibrin-film stents appear to be an excellent candidate for local drug delivery because they can completely and safely cover the stented coronary segment while degrading slowly over 1 to 3 months. This result is important when compared with the poor results of previous studies of synthetic polymer stents.

Animals↗
PubMed1998

Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic three-dimensional computed tomography technique.

OBJECTIVES: The objective of this study was to examine the quantitative response of the adventitial vasa vasorum to balloon-induced coronary injury. BACKGROUND: Recent attention has focused on the role of vasa vasorum in atherosclerotic and restenotic coronary artery disease. However, the three-dimensional anatomy of these complex vessels is largely unknown, especially after angioplasty injury. The purpose of this study was to visualize and quantitate three-dimensional spatial patterns of vasa vasorum in normal and balloon injured porcine coronary arteries. We also studied the spatial growth of vasa vasorum in regions of neointimal formation. A novel imaging technique, microscopic computed tomography, was used for these studies. METHODS: Four pigs were killed 28 d after coronary balloon injury, and four pigs with uninjured coronary arteries served as normal controls. The coronary arteries were injected with a low-viscosity, radiopaque liquid polymer compound. Normal and injured coronary segments were scanned using a microscopic computed tomography technique. Three-dimensional reconstructed maximum intensity projection and voxel gradient shading images were displayed at different angles and voxel threshold values, using image analysis software. For quantitation, seven to 10 cross-sectional images (40 normal and 32 balloon injured cross-sections) were captured from each specimen at a voxel size of 21 microm. RESULTS: Normal vasa vasorum originated from the coronary artery lumen, principally at large branch points. Two different types of vasa were found and classified as first-order or second-order according to location and direction. In balloon-injured coronary arteries, adventitial vasa vasorum density was increased (3.16+/-0.17/mm2 vs. 1.90+/-0.06/mm2, p = 0.0001; respectively), suggesting neovascularization by 28 d after vessel injury. Also, in these injured arteries, the vasa spatial distribution was disrupted compared with normal vessels, with proportionally more second-order vasa vasorum. The diameters of first-order and second-order vasa were smaller in normal compared with balloon-treated coronary arteries (p = 0.012 first-order; p < 0.001, second-order; respectively). The density of newly formed vasa vasorum was proportional to vessel stenosis (r = 0.81, p = 0.0001). Although the total number of vasa was increased after injury, the total vascular area comprised of vasa was significantly reduced in injured vessels compared with normals (3.83+/-0.20% to 5.42+/-0.56%, p = 0.0185). CONCLUSIONS: Adventitial neovascularization occurs after balloon injury. The number of new vessels is proportional to vessel stenosis. These findings may hold substantial implications for the therapy of vascular disease and restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1998

Cis- and trans-acting factors regulating transcription of the BGT1 gene in response to hypertonicity.

We have previously identified a tonicity-responsive enhancer (TonE) in the promoter region of the canine BGT1 gene. TonE mediates hypertonicity-induced stimulation of transcription. Here, we characterize TonE and TonE binding proteins (TonEBPs) to provide a biochemical basis for cloning of the TonEBPs. Mutational analysis applied to both hypertonicity-induced stimulation of transcription and TonEBP binding reveals that TonE is 11 base pairs in length, with the consensus sequence of (C/T)GGAAnnn(C/T)n(C/T). Activity of the TonEBPs increases in response to hypertonicity with a time course similar to that of transcription of the BGT1 gene. Studies with inhibitors indicate that translation, but not transcription, is required for activation of the TonEBPs. Phosphorylation is required for the stimulation of transcription but not for activation of DNA binding by the TonEBPs. In vivo methylation by dimethyl sulfate reveals that the TonE site of the BGT1 gene is protected with a time course like that of activity of the TonEBPs and activation of transcription. Ultraviolet cross-linking indicates that the TonEBPs share a DNA binding subunit of 200 kDa.

Animals↗
PubMed1998

Field isolates of transmissible gastroenteritis virus differ at the molecular level from the Miller and Purdue virulent and attenuated strains and from porcine respiratory coronaviruses.

The diversity in selected regions of the transmissible gastroenteritis virus (TGEV) and porcine respiratory coronavirus (PRCV) genomes was analyzed among known TGEV and PRCV strains and field isolates. The N-terminal half of the spike (S) glycoprotein gene and open reading frames (ORF) 3, 3-1 and 4 were amplified by reverse transcriptase reaction and polymerase chain reaction (RT/PCR), and analyzed using restriction fragment length polymorphism (RFLP) patterns of the amplified DNA. Reference TGEV strains (Miller and Purdue) and a PRCV strain (ISU-1), and TGEV and PRCV field isolates were analyzed. Based on the size of the ORF 3, 3-1 and 4 RT/PCR products, TGEV and PRCV strains could be quickly and easily differentiated into three groups designated TGEV Miller, Purdue types and PRCV. By RFLP analysis of the N-terminal region of the S glycoprotein gene and ORFs 3, 3-1 and 4, TGEV and PRCV strains were differentiated into five groups using the restriction enzyme Sau3AI. Sequence analysis of a PCR product in the ORFs 3, 3-1 and 4 from virulent and attenuated Miller strains demonstrated additional differences in that region which have been correlated with a change in virulence of TGEV isolates.

Animals↗
PubMed1998

Hemodynamic effects of the geometric dimensions of graft vessels in coronary artery bypass graft models.

The objectives of this investigation are to evaluate the rheologic properties in atherosclerotic disease treated with the various coronary artery bypass graft (CABG) models by numerical analysis, we used four different CABG models for the assessment of spatial fluctuation in wall shear stress, pressure variation and mass flow rate with Carreau model and Navier-Stokes equation. Wall shear stress was higher in a naturally tapered model (model 1) and a constant (non-tapered) diameter of the graft vessel the same as the distal LAD (model 4) than in others. Pressure variation along the native coronary artery and graft vessels was higher in a model 4, model 1 than in a reverse tapering model (model 2) and a constant diameter of the graft vessel the same as the proximal LAD (model 3). The mass flow rate of the distal part (kg/sec,.m(o)) was the highest in model 3. This study suggests that in vitro spatial simulation following CABG revealed that small caliber or tapered graft vessels have adverse hemodynamic effects on the native and graft vessels. By this technique it is possible to simulate the optimal distribution of local hemodynamic variables in patients treated with CABG, also to minimize the degeneration of graft vessel.

Computer Simulation↗
PubMed1998

Ultrastructural changes of the internal elastic lamina in experimental hypercholesterolemic porcine coronary arteries.

The internal elastic lamina (IEL) serves as a barrier for cells and macromolecules between the intima and media in the vascular wall. We evaluated the morphological changes and quantitative assessments of the IEL architecture in the coronary circulation of pigs fed with a high cholesterol diet. Transmission electron microscopy (TEM) analysis of the IEL from hypercholesterolemic coronary arteries revealed fragmentation of the IEL associated with a decrease in the thickness. Confocal microscopy and scanning electron microscopy (SEM) revealed an altered pattern characterized by a large oval fenestration in the IEL of hypercholesterolemic vessels. Morphometric analysis of confocal microscopy images demonstrated that the IEL of cholesterol-fed animals were characterized by an increase in the minor diameter of the fenestrae (2.16+/-0.04 microm vs 3.32+/-0.06 microm, p=0.003) and a decrease in the fenestrae density (22,333+/-1,334/mm2 vs 17,552+/-931/mm2, p=0.015) compared to controls. The percentage of the IEL area covered by the fenestrae correlated with the intimal thickness (r=0.79, p=0.004). The immunoreactivity for matrix metalloproteinase-3 (MMP-3) increased in cholesterol-fed coronary arteries, predominantly in the neointima. This study demonstrates experimental hypercholesterolemia induced ultrastructural changes of the IEL in the coronary circulation. The IEL may play an important role in the development of structural changes which characterize the early phase of coronary atherosclerosis.

Animals↗
PubMed1998

Computed numerical analysis of the biomechanical effects on coronary atherogenesis using human hemodynamic and dimensional variables.

The objectives of this investigation were to evaluate biomechanical factors in the atherosclerotic process using human in vivo hemodynamic parameters and computed numerical simulation qualitatively and quantitatively. The three-dimensional spatial patterns of steady and pulsatile flows in the left coronary artery were simulated, using a finite volume method. Coronary angiogram and Doppler ultrasound measurement of the proximal left coronary flow velocity were performed in humans. Inlet wave velocity distribution obtained from in vivo data of the intravascular Doppler study allowed for input of in vitro numerical simulation. Hemodynamic variables, such as flow velocity, pressure and shear stress of the left anterior descending coronary bifurcation site were calculated. We found that there were spatial fluctuation of flow-velocity and recirculation areas at the curved outer wall of the left anterior descending coronary artery, which were due to the differences of flow-velocity and shear stress, especially during the declaration phase of pulsatile flow. This study suggests that rheologic properties may be a part of the atherogenic process in the coronary bifurcated and curved areas.

Biomechanical Phenomena↗
PubMed1998

Experimental hypercholesterolemia induces ultrastructural changes in the elastic laminae of rabbit aortic valve.

Atherosclerosis is the most severe problem in the high-pressure systemic circulation and similar changes also occur in the high-pressure loading valve. This study was designed to test the hypothesis that early atherosclerosis, induced by a high cholesterol diet in rabbits, is characterized by significant ultrastructural change in the elastic laminae of the aortic valve. However, it is not known whether this process is also taking place in the cardiac valve at the early stage of atherosclerosis. Animals were fed either a high cholesterol diet (n = 5) or a control diet (n = 5) for 10-12 weeks. Histologic analysis demonstrated that subendothelial thickening and foam-cell infiltration were evident in the arterialis of aortic valves. Confocal microscopy revealed an altered pattern characterized by fragmentation and disorganization of the arterialis elastic laminae of hypercholesterolemic valves. Computerized digital analysis of the images obtained by confocal scanning microscopy demonstrated that compared to normal valves, the arterialis elastic laminae of hypercholesterolemic valves decreased in percentage of their elastin content (29.03 +/- 1.10% vs. 42.94 +/- 1.35%, p = 0.023). Immunohistochemical staining for matrix metalloproteinase-3 (MMP-3) revealed MMP-3 immunoreactivity was increased in hypercholesterolemic valves, predominantly in the arterialis. This study demonstrated that early atherosclerosis, induced by a high cholesterol diet in rabbits, is characterized by significant ultrastructural change in the elastic laminae of the aortic valve. The arterialis endothelium of the aortic valve may be a more atherosclerosis-prone area compared with the ventricularis. The presence of ultrastructural defect in the elastic laminae may play a role in chronic degenerative change and a resultant valvular dysfunction.

Animals↗
PubMed1997

The structural organization of the human Na+/myo-inositol cotransporter (SLC5A3) gene and characterization of the promoter.

The genomic structure, transcription start site, polyadenylation signals, and promoter of the human Na+/ myo-inositol cotransporter (SLC5A3) gene have been elucidated through cloning, sequencing, mRNA analyses, and reporter gene assays. The gene consists of one promoter and two exons spanning approximately 26 kb. Exon 1 contains 175 bp of 5' untranslated sequence and is 15 kb upstream of exon 2. The 9.5-kb exon 2 contains the entire 2157-bp open reading frame and a large 3' untranslated sequence with seven putative polyadenylation signals. Multiple messages with different-sized 3' untranslated regions can be detected on Northern blots. Hypertonic stress caused mRNA levels, and primarily that of the full-length 9.5-kb transcript, to increase in cultured melanoma cells; ribonuclease protection analysis demonstrated that the transcription start site was the same in stressed as in control cells. The SLC5A3 gene functions in cellular osmoregulation and is expressed in many human tissues including the brain, kidney, and placenta. It is localized to chromosome 21q22.1. An overexpression of the SLC5A3 gene deserves consideration as a factor in the pathophysiology of Down syndrome.

Animals↗
PubMed1997

The canine sodium/myo-inositol cotransporter gene: structural organization and characterization of the promoter.

The sodium/myo-inositol cotransporter (SMIT) is a plasma membrane protein catalyzing transfer of myo-inositol into cells against a considerable concentration gradient using the electrochemical potential of sodium across the cell membrane. Transcription of the SMIT gene is markedly stimulated when cells are exposed to a hypertonic environment resulting in increased abundance of SMIT mRNA and increased SMIT activity. The increased accumulation of myo-inositol protects cells from the deleterious effects of hypertonicity. In an effort toward understanding transcriptional regulation, we cloned canine genomic DNA fragments containing the SMIT gene. The gene is 37 kb in size consisting of 2 exons and a large intron of 25 kb. The entire open reading frame is in the second exon. The promoter of the gene is highly active due to a GC-rich sequence. Ribonuclease protection assay using a riboprobe complementary to the 5' end of the gene confirmed that the promoter of the gene is stimulated by hypertonicity. The promoters and regulatory sequences of the SMIT gene and the betaine transporter gene, another gene regulated by hypertonicity, appear to be different.

Animals↗
PubMed1997

Kidney cell survival in high tonicity.

The kidney medulla of mammals undergoes large changes in tonicity in parallel with the tonicity of the final urine that emerges from the kidney at the tip of the medulla. When the medulla is hypertonic, its cells accumulate the compatible osmolytes myo-inositol, betaine, taurine, sorbitol and glycerophosphorylcholine. The mechanisms by which the compatible osmolytes are accumulated have been explored extensively in kidney-derived cells in culture. Myo-inositol, betaine and taurine are accumulated by increased activity of specific sodium-coupled transporters, sorbitol by increased synthesis of aldose reductase that catalyses the synthesis of sorbitol from glucose. Glycerophosphorylcholine accumulates primarily because its degradation is reduced in cells in hypertonic medium. cDNAs for the cotransporters and for aldose reductase have been cloned and used to establish that hypertonicity increases the transcription of the genes for the cotransporters for myo-inositol, betaine and for aldose reductase. The region 5' to the promoter of the gene for the betaine cotransporter and for aldose reductase confer osmotic responsiveness to a heterologous promoter. The 12-bp sequence responsible for the transcriptional response to hypertonicity has been identified in the 5' region of the gene for the betaine cotransporter.

Animals↗
PubMed1997

Kinetics and osmoregulation of Na(+)-and Cl(-)-dependent betaine transporter in rat renal medulla.

Betaine is one of the major organic osmolytes that accumulate in the renal medulla in response to high extracellular tonicity. Recent studies in MDCK cells have shown that betaine is taken up by an Na(+)- and Cl(-)-dependent transporter located on the basolateral membrane. We demonstrate here the presence of Na(+)-Cl(-)-dependent betaine transporter(s) in tubule suspensions prepared from the rat outer and inner medulla. The betaine transport activity was two to three times higher in the inner medulla compared with the outer medulla. The removal of Na+ and Cl- reduced betaine uptake in the outer medullary tubules by 86% and 82%, respectively. The betaine uptake was decreased by 39% in hypotonic buffer (189 mosmol/ kgH2O) and increased by 82% in hypertonic buffer (545 mosmol/kgH2O), compared with isotonic buffer (308 mosmol/ kgH2O). Kinetic studies of Na(+)-dependent betaine uptake in the outer medullary tubules revealed both a low- and a high-affinity component as follows: low-affinity and high volume component with Michaelis constant (K(m)1) of 8.6 mM and maximal uptake rate (Vmax1) of 112 pmol.microgram protein-1.h-1; and a low-volume and high-affinity component with K(m)2 of 0.141 mM and Vmax2 of 10 pmol. microgram protein-1.h-1. To investigate whether the Na(+)-Cl(-)-dependent betaine transporter is regulated by tonicity in vivo, we quantitated its mRNA in rat renal cortex and outer and inner medulla using both canine and rat Na(+)-Cl(-)-dependent betaine transporter cDNA probes. A single band of 3.0 kb was seen in the Northern blots prepared from both outer and inner medulla, but not in the cortex. Water deprivation for 3 days increased the abundance of this mRNA in the outer and inner medulla by 140% and 170%, respectively, but did not affect its expression in the cortex. In conclusion, Na(+)-Cl(-)-dependent betaine transporter(s) is present in rat outer and inner medullary tubules, and betaine transporter mRNA abundance is regulated by the hydration state in vivo.

Animals↗
PubMed1997

Osmolarity in renal medulla of transgenic mice regulates transcription via 5'-flanking region of canine BGT1 gene.

Betaine is a major compatible osmolyte accumulated in the mammalian kidney medulla and in Madin-Darby canine kidney cells in response to hypertonicity. The accumulation is the result of an increase in maximal velocity of the Na(+)- and Cl-coupled betaine transporter designated BGT1. We have previously cloned the canine BGT1 gene and identified a tonicity-responsive enhancer element (TonE) in its 5'-flanking region. Here we report studies of transgenic mice that have in their genome 2.4 kb of the 5'-flanking region of the canine BGT1 gene in front of a chloramphenicol acetyl-transferase (CAT) reporter. Expression of CAT mRNA was detected only in the renal medulla and was increased by experimental manipulations that increase the tonicity of the renal medulla and decreased by manipulations that decrease medullary tonicity. We conclude that the 2.4-kb 5'-flanking region of the BGT1 gene mediates an increase in transcription in response to hyperosmolarity in the renal medulla.

Animals↗
PubMed1997

Inhibition of neointimal proliferation of rat carotid artery by sulodexide.

Sulodexide, a glycosaminoglycan-containing compound, is known to have an antiproliferative effect on vascular smooth-muscle cells, in vitro, as well as antithrombotic and fibrinolytic effects. But there are few reports about the effect of neointimal proliferation in vivo. In this study, we examined whether Sulodexide was effective in the inhibition of neointimal proliferation after vascular injury. Ten-week-old Sprague-Dawley rats were subjected to vascular injury by endothelial denudation of the common carotid artery by using a balloon catheter. They were then allocated randomly into a control group (saline 2 ml for 3 days, and then 1 ml for 18 days, IM) and a treated group (Sulodexide 10 mg/kg/day for 3 days, and then 4 mg/kg/day for 18 days, IM). Three weeks after vascular injury, we analyzed the neointimal proliferation using morphometry. The neointimal proliferation was significantly reduced in the treated group compared to the control group (Ratio of neointimal area to medial area; 118.39 +/- 6.80% in the treated group, 177.25 +/- 17.25% in the control group). This result showed that Sulodexide might be effective in reducing the rate of restenosis after balloon angioplasty.

Angioplasty, Balloon↗
PubMed1997

The angiotensin converting enzyme genetic polymorphism in acute coronary syndrome--ACE polymorphism as a risk factor of acute coronary syndrome.

The deletion polymorphism of angiotensin converting enzyme (ACE) genotype has been reported as an independent risk factor for the development of myocardial infarction (MI). However there are conflicting data showing no relationship between the ACE genotype and coronary artery disease. The present study was performed to investigate the correlation between ACE genetic polymorphism and acute coronary syndrome by comparing the distribution of ACE genotypes and ACE activities in patients with acute MI and unstable angina with those in control group. The frequency of genotype DD was significantly higher in patients with acute coronary syndrome than in controls. Logistic regression analysis showed that ACE polymorphism affected the development of acute coronary syndrome in recessive pattern of D allele. When we divided the patients into MI and unstable angina groups, the frequencies of genotype DD and D allele were significantly higher in unstable angina group than in MI or control groups. In the patients with MI, the frequency of D allele was significantly higher in patients without previous angina than in those with previous angina. There was no significant difference in ACE genotype or allelic frequency according to the severity of coronary lesions. The ACE genotype was associated with marked differences of ACE activity, but there was no difference between the patient and control groups for each genotype. In conclusion, the genotype DD of ACE gene associated with acute coronary syndrome, but not with the severity of coronary artery lesion. These results showed that the genotype DD of ACE gene might be associated with acute coronary syndrome by another mechanism rather than the coronary atherosclerosis.

Acute Disease↗
PubMed1996

Regulation of the myo-inositol and betaine cotransporters by tonicity.

Cells of the hypertonic renal medulla accumulate high concentrations of the non-perturbing osmolytes myo-inositol, betaine, and taurine, and are thereby protected from the perturbing effects of hypertonicity. Kidney-derived MDCK cells accumulate high levels of these three non-perturbing osmolytes when cultured in hypertonic medium and have been used to study their accumulation. The increase in the intracellular concentration of these non-perturbing osmolytes is the result of an increase in the abundance of the mRNA for the specific cotransporter for each osmolyte and the ensuing increase in the activity of the three specific sodium coupled transporters. The increased abundance of mRNA for the myo-inositol and the betaine cotransporters is driven by an increase in the rate of transcription of their genes. We have identified a 13 basepair cis-acting element in the 5' flanking region of the gene for the betaine cotransporter. The element is an enhancer that mediates the transcriptional response to hypertonicity. The protein(s) that binds to the tonicity responsive element is much more active in hypertonic than in isotonic cells, and is in all likelihood the mediator of the transcriptional response to changes in tonicity.

Animals↗