Atherosclerotic Human Coronary Arteries Research Articles

Human Urotensin II as a Link between Hypertension and Coronary Artery Disease

Hypertension is a well-known risk factor for atherosclerosis, but the molecular mechanisms that link elevated blood pressure to the progression of atherosclerosis remain unclear. Human urotensin II (U-II), the most potent endogenous vasoconstrictor peptide identified to date, and its receptor (UT receptor) are involved in the etiology of essential hypertension. In patients with essential hypertension, U-II infused into the forearm brachial artery has been shown to induce vasoconstriction. Recent studies have demonstrated elevated plasma U-II concentrations in patients with essential hypertension, diabetes mellitus, atherosclerosis, and coronary artery disease. U-II is expressed in endothelial cells, macrophages, macrophage-derived foam cells, and myointimal and medial vascular smooth muscle cells (VSMCs) of atherosclerotic human coronary arteries. UT receptors are present in VSMCs of human coronary arteries, the thoracic aorta and cardiac myocytes. Lymphocytes are the most active producers of U-II, whereas monocytes and macrophages are the major cell types expressing UT receptors, with relatively little receptor expression in foam cells, lymphocytes, and platelets. U-II accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human endothelial cells, U-II promotes cell proliferation and up-regulates type 1 collagen expression. U-II also activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and plasminogen activator inhibitor-1 in human VSMCs, and stimulates VSMC proliferation with synergistic effects observed when combined with oxidized low-density lipoprotein, lysophosphatidylcholine, reactive oxygen species or serotonin. These findings suggest that U-II plays key roles in accelerating the development of atherosclerosis, thereby leading to coronary artery disease.

Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli

Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein. Several studies have reported increased AIF-1 expression in activated macrophages and have implicated AIF-1 as a marker of activated macrophages. However, the function of AIF-1 in macrophages and the mechanism whereby it participates in macrophage activation are unknown at this time. Immunohistochemical analysis colocalized AIF-1 expression with CD68-positive macrophages in atherosclerotic human coronary arteries. Subsequent experiments were designed to determine a role for AIF-1 in macrophage activation in response to atherogenic stimuli. Stimulation of human and murine macrophages with oxidized LDL significantly increased AIF-1 expression above basal levels. Stable transfection of AIF-1 small interfering RNA (siRNA) in macrophages reduced AIF-1 protein expression by 79% and reduced macrophage proliferation by 52% (P < 0.01). Inhibition of proliferation was not due to induction of apoptosis. Sequences that did not knock down AIF-1 expression had no effect on proliferation. AIF-1 siRNA expression reduced macrophage migration by 60% (P < 0.01). Both proliferation and migration of siRNA-expressing macrophages could be restored by adenoviral expression of AIF-1 (P < 0.001 and 0.005, respectively), suggesting a tight association between AIF-1 expression and macrophage activation. Phosphorylation of Akt, p44/42 MAPK, and p38 kinase were significantly reduced in siRNA macrophages challenged with oxidized LDL (P < 0.05). Phosphorylation of p38 kinase was significantly inhibited in siRNA macrophages stimulated with T lymphocyte conditioned medium (P < 0.05). These data indicate that AIF-1 mediates atherogenesis-initiated signaling and activation of macrophages.

Activation of telomerase and expression of human telomerase reverse transcriptase in coronary atherosclerosis

Introduction Considerable research on telomerase on human neoplastic and normal long-lived proliferative tissues has emerged. We explored the expression of telomerase in atherosclerotic human epicardial coronary arteries. Methods Forty discrete human coronary arterial segments obtained from 19 heart transplant recipients were classified into nonatherosclerotic and atherosclerotic groups based on coronary angiography and histological examination. PCR-ELISA-based telomeric repeat amplification protocol (TRAP), and immunohistochemical analyses were conducted to determine the functional activity and cell-specific expression of telomerase. Results Seventy percent of atherosclerotic coronary arteries exhibited positive telomerase activity, and the reactivation incidence reached fourfold higher than that of controls ( P=.007). The telomerase catalytic protein, human telomerase reverse transcriptase (hTERT), was expressed in 88% of atherosclerotic tissues, a fivefold higher frequency compared with that of the controls. There was also a correlation of hTERT expression with the level of telomerase bioactivity ( P=.017) and with the severity of atherosclerotic grade ( P<.001). In comparison with the immunostaining of mitotic antigen, Ki-67, we found an association of hTERT expression with actively cycling cells in early lesions but with quiescent cells in late advanced atherosclerotic stages. Conclusions The up-regulation of telomerase and its catalytic hTERT protein during stages of atherosclerotic evolution may implicate a role of telomerase in vascular remodeling underlying atherogenesis.

Expression of urotensin-II in human coronary atherosclerosis

The vasoactive peptide urotensin-II (U-II) is best known for its ability to regulate peripheral vascular and cardiac contractile function in vivo, and recent in vitro studies have suggested a role for the peptide in the control of vascular remodeling by inducing smooth muscle proliferation and fibroblast-mediated collagen deposition. Therefore, U-II may play a role in the etiology of atherosclerosis. In the present study we sought to determine the expression of U-II in coronary arteries from patients with coronary atherosclerosis and from normal control subjects, using immunohistochemistry and in situ hybridization. In normal coronary arteries, there was little expression of U-II in all types of cells. In contrast, in patients with coronary atherosclerosis, endothelial expression of U-II was significantly increased in all diseased segments ( P < 0.05). Greater expression of U-II was noted in endothelial cells of lesions with subendothelial inflammation or fibrofatty lesion compared with that of endothelial cells underlined by dense fibrosis or minimal intimal thickening. Myointimal cells and foam cells also expressed U-II. In most diseased segments, medial smooth muscle cells exhibited moderate expression of U-II. These findings demonstrate upregulation of U-II in endothelial, myointimal and medial smooth muscle cells of atherosclerotic human coronary arteries, and suggest a possible role for U-II in the pathogenesis of coronary atherosclerosis.

Frontiers in Cardiovascular Magnetic Resonance

Cardiovascular magnetic resonance (MR) is emerging as a multipurpose imaging modality for the assessment of cardiovascular disease in general and ischemic heart disease in particular. Currently, the pace of innovation is rapid, and the modality is changing from one that is used primarily as a research tool to one that is increasingly used in routine clinical practice. The process of innovation includes not only improvements in scanner hardware, such as coil and gradient technology, and the development of new contrast agents but also the development of novel pulse sequences. The concept of the pulse sequence, in which programming changes at the scanner can lead to fundamental changes in activating tissue, is unique to MR and gives this modality the potential to assess a vast number of biological parameters. Cardiovascular MR promises to play an important clinical and investigational role in both vascular and cardiac systems. Current and potential future applications of cardiovascular MR will be discussed with a particular focus on ischemic heart disease. Multidetector-row computed tomography, another promising and complementary noninvasive imaging technology, will be discussed briefly in relation to cardiovascular MR for the assessment of atherothrombotic disease. ### Nomenclature and Evolving Imaging Assessment Atherothrombosis is a systemic or multiterritory arterial disease that primarily affects the large- and medium systemic arteries, including the aorta and the carotid, coronary, and peripheral arteries. Although the epicardial coronary arteries appear to be the most susceptible to atherothrombosis,1,2 intramyocardial arteries are relatively resistant. The concept of multiterritory atherothrombosis has been addressed in 2 large studies of symptomatic patients that showed that at entry into the studies, 3% to 8% had symptomatic atherothrombotic disease in all 3 main arterial districts and 23% to 32% had disease in 2 districts.3,4 From a structural point of view, the 4 main components of the atherothrombotic plaques are as follows: (1) fibrocellular, …

Principal component analysis of elements in atherosclerotic human coronary arteries

Principal component analysis was applied to identify normal and pathological structures using combinations of levels of phosphorus, sulphur, chlorine, potassium and calcium in early stages of atherosclerotic coronary arteries. An inverse correlation was found between the combination of Ca–P, and that of S–Cl–K. This finding points towards the presence of smaller calcified deposits in an early phase of atherosclerosis in the human coronary artery. A possible location of cholesterol or some other carbon-based materials could also be identified. Further, a histogram method proved to be useful for characterising calcified structures of Ca/P mass ratio lower than that of hydroxyapatite. An empirical formula of (1−n)Ca3(PO4)2·nAm(PO4) is suggested to explain composition of these calcified structures.

Letter Regarding Article by Korshunov and Berk, “Strain-Dependent Vascular Remodeling: The ‘Glagov Phenomenon’ Is Genetically Determined”

To the Editor: Drs Korshunov and Berk1 described the modulation of vascular remodeling in response to a sudden decrease of shear stress induced by partial ligation of the carotid artery of different mouse strains. Although a similar study was previously conducted with similar mouse strains in which the carotid artery was totally occluded,2 Korshunov and Berk argued that their partial ligation model is more relevant to human carotid intima-media thickness and coronary atherosclerosis and concluded from their measurements that the Glagov phenomenon has a genetic background. To strengthen the relevance of their data, the authors compared their results—outward remodeling under low flow conditions—to our data in human atherosclerotic coronary arteries.3 Indeed, we found that in segments with lumen preservation because of outward vascular remodeling, atherosclerotic plaques were observed at relatively low shear stress regions.3 Because vascular remodeling is defined as an average over the cross …

Expression, localisation and function of ACE and chymase in normal and atherosclerotic human coronary arteries

The expression, localisation and function of enzymes responsible for the local formation of angiotensin II in atherosclerotic and non-atherosclerotic human coronary arteries were studied. Human epicardial coronary arteries expressed mRNA for both ACE and chymase. Immunohistochemical studies revealed that ACE was localised to the vascular endothelium, and to a lesser extent the medial smooth muscle cells, in both large and small arteries. Chymase was detected in both types of vessel but was shown to be associated with mast cells. The contractions to angiotensin I in large arteries were inhibited only by a combination of quinaprilat and soyabean trypsin inhibitor. In the intramyocardial arteries the response to angiotensin I was markedly inhibited in the presence of chymostatin. These findings demonstrate that a dual pathway for the synthesis of angiotensin II is active in diseased and non-diseased coronary arteries.

Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries

We detected urotensin-II-like immunoreactivity in the endothelium of normal human blood vessels from heart, kidney, placenta, adrenal, thyroid and umbilical cord. Immunoreactivity was also detected in endocardial endothelial and kidney epithelial cells. In atherosclerotic coronary artery, immunoreactivity localized to regions of macrophage infiltration. Urotensin-II constricted human atherosclerotic epicardial coronary arteries with pD 2 = 10.58 ± 0.46 (mean ± S.E.M.) and E max = 11.4 ± 4.2% KCl and small coronary arteries with pD 2 = 9.25 ± 0.38 and E max = 77 ± 16% KCl. Small coronary arteries clearly exhibited a greater maximum response to urotensin-II than epicardial vessels. This enhanced responsiveness may be of importance in heart failure, where circulating concentrations of U-II are increased, or in atherosclerosis where focally up-regulated urotensin-II production may act down stream to produce significant vasospasm, compromising blood flow to the myocardium. We conclude that urotensin-II is a locally released vasoactive mediator that may be an important regulator of blood flow particularly to the myocardium and may have a specific role in human atherosclerosis.

A finite element model for performing intravascular ultrasound elastography of human atherosclerotic coronary arteries

Intravascular ultrasound (US) elastography measures in an artery the arterial radial strain and displays it in an elastogram. An elastogram adds diagnostic information, such as the proneness of a plaque to rupture and its material composition. However, radial strain depends upon the material properties of an artery, including geometry and used catheter position. Therefore, there is not always a one-to-one correspondence between radial strain and rupture-proneness or material composition. Both the dependence and the correspondence can be quantified after a proper finite element model (FEM) is available. Therefore, this paper proposes a FEM and shows that it can model the arterial strain behavior. Its modelling capability was evaluated by comparing simulated with measured elastograms. Measured elastograms were processed from radiofrequency (RF) data obtained in vitro from six objects: a vessel-mimicking phantom and five excised human atherosclerotic coronary arteries. A FEM was created for each object and used to simulate an elastogram; the material properties and geometry of the FEM were obtained from the histology of the object. Comparison was performed upon high strain regions (HStR), because these regions have proven to contain plaques that show the hallmarks of vulnerable plaques. Eight HStR were automatically identified from the five arteries. Statistical tests showed that there was no significant difference between simulated and corresponding measured elastograms in location, surface area or mean strain value of a HStR. The results demonstrate that the FEM can simulate elastograms measured from arteries. As such, the FEM may help in quantifying strain-dependencies and assist in tissue characterization by reconstructing a Young's modulus image from a measured elastogram. (E-mail: r.baldewsing@erasmusmc.nl)

1064-185 Systemic infection lead to infiltration of macrophages in adventitia of human atherosclerotic coronary arteries: Clue to triggering effect of acute infections on acute coronary syndromes

1064-185 Systemic infection lead to infiltration of macrophages in adventitia of human atherosclerotic coronary arteries: Clue to triggering effect of acute infections on acute coronary syndromes

Classification of arterial plaque by spectral analysis in remodelled human atherosclerotic coronary arteries

We aimed to characterise and to identify the predominant plaque type in vivo using unprocessed radiofrequency (RF) intravascular ultrasound (US) backscatter, in remodelled segments of human atherosclerotic coronary arteries. A total of 16 remodelled segments were identified using a 30-MHz intravascular ultrasound (IVUS) scanner in vivo. Of these, 9 segments were classified as positively remodelled (> 1.05 of the total vessel area in comparison with the proximal and distal reference segments) and 7 as negatively remodelled (< 0.95 of reference segment area). Spectral parameters (maximum power, mean power, minimum power and power at 30 MHz) were determined and plaque type was defined as mixed fibrous, calcified or lipid-rich. Positively remodelled segments had a larger total vessel area (16.5 ± 1.1 mm 2 vs. 8.7 ± 0.9 mm 2, p < 0.01) and plaque area (7.3 ± 1.1 mm 2 vs. 4.4 ± 0.8 mm 2, p = 0.05) than negatively remodelled segments. Both positively and negatively remodelled segments had a greater percentage of fibrous plaque ( p < 0.01) than calcified or lipid-rich plaque. Comparing positively and negatively remodelled segments, there was no significant difference between the proportion of fibrous, calcified or lipid-rich plaque. We have been able to characterise and to identify plaque composition in vivo in human atherosclerotic coronary arteries. Our data suggest that remodelled segments are predominantly composed of fibrous plaque, as identified by RF analysis, although plaque composition is similar, irrespective of the remodelling type. (E-mail: a.mcleod@ed.ac.uk)

Finite element modeling and intravascular ultrasound elastography of vulnerable plaques: parameter variation

Background and goal: More than 60% of all myocardial infarction is caused by rupture of a vulnerable plaque. A vulnerable plaque can be described as a large, soft lipid pool covered by a thin fibrous cap. Plaque material composition, geometry, and inflammation caused by infiltration of macrophages are considered as major determinants for plaque rupture. For diagnostic purposes, these determinants may be obtained from elastograms (i.e. radial strain images), which are derived from intravascular ultrasound (IVUS) measurements. IVUS elastograms, however, cannot be interpreted directly as tissue component images, because radial strain depends upon plaque geometry, plaque material properties, and used catheter position. To understand and quantify the influence of these parameters upon measured IVUS elastograms, they were varied in a finite element model (FEM) that simulates IVUS elastograms of vulnerable plaques. Materials and methods: IVUS elastography measurements were performed on a vessel mimicking phantom, with a soft plaque embedded in a hard wall, and an atherosclerotic human coronary artery containing a vulnerable plaque. Next, FEMs were created to simulate IVUS elastograms of the same objects. In these FEMs the following parameters were varied: Young's modulus ( E), Poisson's ratio ( ν) in range 0.49–0.4999, catheter position (translation of 0.8 mm), and cap thickness ( t) in range 50–350 μm. Hereby the resulting peak radial strain (PRS) was determined and visualized. Results: Measured static E for phantom was 4.2 kPa for plaque and 16.8 kPa for wall.Variation of E-wall in range 8.4–33.2 kPa and/or E-plaque in range 2.1–8.4 kPa using the phantom FEM, gave a PRS variation of 1.6%, i.e. from 1.7% up to almost 3.3%; for variation in ν this was only 0.07%, i.e. from 2.37% up to 2.44%. Variation of E-lipid in range 6.25–400 kPa and E-cap in range 700–2300 kPa using the artery FEM, gave a PRS variation of 3.1%, i.e. from 0.6% up to 3.7%. The PRS was higher for lower E-lipid and E-cap; it was located at a shoulder of the lipid pool. Variation of ν gave only a variation of 0.17%. Variation of t and E-cap resulted in a PRS variation of 1.4%, i.e. from 0.3% up to 1.7%; thinner and weaker caps gave higher PRS. Catheter position variation changed radial strain value. Conclusions: Measured IVUS elastograms of vulnerable plaques depend highly upon the Young's modulus of lipid and cap, but not upon the Poisson's ratio. Different catheter positions result in different IVUS elastograms, but the diagnostically important high strain regions at the lipid shoulders are often still detectable. PRS increases when cap weakens or cap thickness decreases.

Testing endothelial vasomotor function: nitric oxide, a multipotent molecule.

The initial description in 1980 by Furchgott and Zawadzki1 of endothelium-derived vasodilator factor has stimulated more than 2 decades of intense research to delineate the basic biology of the endothelium and its importance in the clinical setting.2 Endothelium-derived vasodilator factor has been identified as nitric oxide (NO).2 It is formed in endothelial cells from the amino acid l-arginine by endothelial isoform of NO synthase (eNOS), which is the product of the NOS3 gene.2,3 In addition to producing NO constitutively, the enzyme may be stimulated to increase NO synthesis by a variety of physiological agonists, shear stress, and pharmacological agents. Although discovered as a vasodilator, NO mediates many of the protective functions of the endothelium.4 It limits vascular recruitment of leukocytes by inhibiting the expression of proinflammatory cytokines, chemokines, and leukocyte adhesion molecules.2,4 It inhibits vascular smooth muscle proliferation and platelet adhesion and aggregation.2,4 NO also inhibits the production of tissue factor, a molecule that plays a critical role in the propensity of disrupted atherosclerotic plaques to cause intravascular thrombosis.5 In the setting of risk factors and experimental atherosclerosis, loss of the biological activity of endothelium-derived NO is accompanied by other alterations in endothelial phenotype that further increase the propensity for vasoconstriction, thrombosis, inflammation, and cellular proliferation in the vascular wall.6 Thus, endothelial dysfunction has the potential to contribute to key events in the course of human atherosclerosis. The experimental observations of Furchgott and others have stimulated translational research to elucidate the importance of endothelium-dependent vasodilation in human coronary atherosclerosis. Accordingly, Ludmer and colleagues7 administered the endothelium-dependent dilator acetylcholine into the coronary arteries of subjects undergoing cardiac catheterization. Acetylcholine induced dilation of normal epicardial coronary arteries but induced abnormal vasoconstriction, indicative of endothelial dysfunction, in patients with angiographic evidence of …

Betacellulin and amphiregulin induce upregulation of cyclin D1 and DNA synthesis activity through differential signaling pathways in vascular smooth muscle cells.

Activation of EGF receptors is closely involved in vascular proliferative diseases. The signaling mechanisms of EGF ligands, including betacellulin (BTC) and amphiregulin (AR), are poorly understood. We examined how BTC and AR induced DNA synthesis activity in primary cultures of human thoracic aortic smooth muscle cells (HTASMCs). BTC induced phosphorylation of all four EGF receptors present on HTASMCs: ErbB1, ErbB2, ErbB3, and ErbB4. BTC rapidly induced the phosphorylation of Akt, GSK3alpha/beta, and two FoxO factors, FKHR and AFX, in a dose- and time-dependent manner. BTC increased nuclear beta-catenin accumulation. BTC increased cyclin D1 mRNA, cyclin D1 protein, and DNA synthesis activity. Pretreatment with the phosphatidylinositol 3'-kinase (PI 3'-kinase) inhibitor wortmannin suppressed BTC-induced cyclin D1 mRNA and protein and DNA synthesis activity. In contrast, AR, a specific ErbB1 ligand, induced sustained ERK1/2 and Elk1 phosphorylation, increased cyclin D1 mRNA and protein, and increased DNA synthesis activity. AR did not produce any changes in Akt phosphorylation. Pretreatment with PD98059 suppressed AR-induced cyclin D1 mRNA and protein. Thus, the PI 3'-kinase/Akt/GSK/FoxO/beta-catenin pathway could be the major signaling cascade for BTC-induced upregulation of cyclin D1 protein, whereas a sustained ERK/Elk1 activation could be the major signaling cascade for AR-induced upregulation of cyclin D1 protein in HTASMCs. Moreover, immunohistochemical staining revealed that that BTC, ErbB1, and ErbB4 are upregulated in the plaques of human atherosclerotic coronary arteries. Taken together, BTC and AR could be potent growth factors in proliferative vascular diseases.

Immunohistochemical localization of endothelial cell-derived lipase in atherosclerotic human coronary arteries.

A novel lipoprotein lipase (LPL)-like gene, endothelial cell-derived lipase (EDL), was recently cloned from vascular endothelial cells. The presence of LPL in the vascular wall has been implicated in the progression of atherosclerosis through the bridging function between lipoprotein particles and matrix proteoglycans to enhance lipoprotein uptake into the vascular wall. The aim of this study was to investigate the local expression of EDL in human coronary arteries. Human coronary arterial specimens from 10 autopsied cases were examined by immunohistochemistry with polyclonal antibodies against specific synthetic EDL peptides. Immunohistochemical analysis revealed that EDL was expressed in endothelial cells and medial smooth muscle cells in non-atherosclerotic coronary arteries. In addition, EDL was expressed in infiltrating cells within atheromatous plaques as well as endothelial and smooth muscle cells. Double labeling immunofluorescence confirmed EDL positive-cells were endothelial cells, smooth muscle cells and macrophages. EDL immunoreactivity was also detected in neovasculature within atheromatous plaques in atherosclerotic coronary arteries. These results suggest that EDL may have unique functional roles in the pathogenesis of coronary artery diseases such as atherosclerosis as well as in lipid metabolism in the vessel wall.

Haptoglobin elutes from human atherosclerotic coronary arteries—a potential marker of arterial pathology

Background: Molecules which egress from atherosclerotic arteries may function as plasma markers of arterial pathology, but such egress has not been proven with living human coronary arteries. We hypothesised that proteins eluting from the arterial wall may discriminate between atherosclerotic and non-atherosclerotic coronary arteries. Methods and results: During cardiac bypass surgery, 155 sequential fractions of antegradely flushed coronary cardioplegia solution were collected by balloon-cuffed catheter from the coronary sinus in subjects with angiographically extensive ( n=30) or minor ( n=7) coronary disease. Although plasma was the major source of protein in heavily blood-contaminated samples, under conditions of low blood contamination (<0.5 mg/ml red cell Haemoglobin) coronary circulation-derived protein was detected. N-terminal sequencing of a major 40 kDa band detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated 100% homology with beta chain of Haptoglobin (Hpt). Comparison of perfusates from patients with and without significant coronary disease found that the concentration of Hpt was markedly increased in perfusates from atherosclerotic coronary arteries (0.099±0.017 μg Hpt/μg Hb) relative to controls (0.016±0.008 μg Hpt/μg Hb, P=0.0027). Analysis of peripheral plasma samples of the same subjects, and of a separate cohort of patients, confirmed greater Hpt in those with angiographic coronary disease than in those without disease. Conclusions: Proteins such as Hpt elute from the human coronary vascular bed and may differentiate between arteries with minor or extensive atherosclerosis. Although the suitability of Hpt as a circulating plasma marker for atherosclerosis remains to be established, the approach used in the present study may permit identification of diverse plasma-detectable markers of atherosclerosis, and the subsequent non-invasive evaluation of in vivo arterial pathology.

Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in vascular smooth muscle cells

Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth factor receptor (FGFR)2 IIIb, is located in many types of epithelial cells and is activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10) that are predominantly synthesized by mesenchymal cells. In the early stage of atherosclerosis, vascular smooth muscle cells (VSMC) transform from a contractile to a synthetic phenotype, proliferate and migrate into the intima. Previously, FGF-7 mRNA expression was reported in VSMC, but KGFR mRNA was not detected. In the present study, we attempted to determine whether KGFR is localized in VSMC cultured from rat aorta and VSMC in human normal and atherosclerotic coronary arteries. Expression of KGFR mRNA and its protein was detected in cultured rat VSMC by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Immunohistochemically, KGFR was localized in the VSMC of the outer layer of the media in normal human coronary arteries. Furthermore, it was localized in the VSMC of the media and thickened intima of atherosclerotic arteries. Recombinant FGF-7 and/or FGF-10 proteins stimulated the growth of cultured rat VSMC. These findings indicate that KGFR localized in VSMC may contribute to the proliferation of VSMC in normal and atherosclerotic arteries.

P3453 Mast cells in human atherosclerotic coronary arteries store and secrete basic fibroblast growth factor: association with neovascularization and plaque progression

P3453 Mast cells in human atherosclerotic coronary arteries store and secrete basic fibroblast growth factor: association with neovascularization and plaque progression

P2202 Systemic infection leads to infiltration of macrophages in adventitia of human atherosclerotic coronary arteries: clue to triggering effect of acute infections on acute coronary syndromes

P2202 Systemic infection leads to infiltration of macrophages in adventitia of human atherosclerotic coronary arteries: clue to triggering effect of acute infections on acute coronary syndromes