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Betacellulin (BTC), a new member of the EGF family, has been reported to be a potent mitogen for rat vascular smooth muscle cells (SMCs). BTC mRNA is known to be expressed in several human organs. However, the localization of BTC in human vascular tissues has not yet been clarified. We investigated whether or not BTC protein is involved in the pathogenesis of human atherosclerosis. Recombinant human BTC showed a mitogenic activity on cultured human aortic SMCs by measuring [3H]thymidine incorporation. The immunohistochemical localization of BTC, SMCs, macrophages, EGF receptors and ErbB4 was examined in autopsied human aortas. BTC was detected in both intimal and medial SMCs of the aortic wall. The percentage of BTC-positive medial SMCs in early types of atherosclerotic lesions decreased with age, but in adult, it was significantly higher in advanced types than in early types of atherosclerotic lesions. BTC-positive SMCs were predominantly localized in the medial side of the intima. Furthermore, numerous BTC-positive SMCs and macrophages were observed around the core lesion of atherosclerotic plaques. Receptors for BTC, EGF receptor and ErbB4, were expressed on SMCs, suggesting that BTC is associated with EGF receptor family-mediated signaling. BTC is produced in human aortic tissue and might play important roles in atherogenesis.

We demonstrated a continuous intracoronary infusion of acetylcholine-induced marked decrease of coronary blood flow estimated by intracoronary Doppler flow wire without significant epicardial coronary narrowing. This case can be called a patient with microvas cular vasospastic angina.

To clarify the physiological roles of CD36 as an oxidized low density lipoprotein (OxLDL) receptor, we analyzed the monocyte-derived macrophages from normal and two CD36-deficient subjects, since we identified the molecular abnormalities (Kashiwagi, H., Y. Tomiyama, Y. Kosugi, M. Shiraga, R. H. Lipsky, Y. Kanayama, Y. Kurata, and Y. Matsuzawa 1994. Blood. 83:3545-3552; and Kashiwagi, H., Y. Tomiyama, S. Honda, S. Kosugi, M. Shiraga, N. Nagao, S. Sekiguchi, Y. Kanayama, Y. Kurata, and Y. Matsuzawa. 1995. J. Clin. Invest. 95:1040-1046). Scatchard analysis of 125I-OxLDL binding showed a linear plot and the maximum binding was lower by approximately 40% in the macrophages from subjects with CD36 deficiency than those from normal controls. Competition studies showed that the uptake of 125I-OxLDL was suppressed by OKM5, an antibody against CD36, by 53% in normal control macrophages, but not in the CD36-deficient macrophages. After incubation with OxLDL for 24 h, cholesteryl ester mass accumulation was reduced by approximately 40% in the macrophages from CD36-deficient subjects than those from normal controls. These results suggest that CD36 is one of the physiological receptors for OxLDL. Since specific binding of OxLDL was only reduced by approximately 40% in spite of the complete deficiency of CD36, several other receptors also may have some role in OxLDL uptake. Further studies will be needed to assess the quantitative role of CD36 in foam cell formation in vivo.

A patient with hepatocellular carcinoma, associated segmental portal vein thrombosis, and accompanying pneumobilia, developed a liver abscess and sepsis following transcatheter chemoembolization (TCE). It was believed that the combination of bile duct necrosis after arterial occlusion and pneumobilia led to ascending enteric infection and seeding of the necrotic tumor, which ultimately led to fatal outcome. We conclude that TCE is contraindicated in such cases.

Abstract —CD36 has been reported to be a receptor for oxidized LDL (Ox-LDL). In our previous study, the uptake of Ox-LDL in CD36-deficient macrophages was reduced by approximately 50% compared with that in control macrophages, suggesting an important role of CD36 as a receptor for Ox-LDL in humans. In the current study, we examined the immunohistochemical localization of CD36 in human aorta in comparison with that of scavenger receptor class A type I and type II (SRA). Cryostat sections were made from aortic tissues. For immunohistochemical staining, the following antibodies were used: (1) FA6-152, anti-CD36 antibody, and (2) SRI-2, which recognizes both type I and type II SRAs. Immunohistochemical staining for CD36 and SRA was performed using labeled streptavidin method. In macrophages scattered in aortic walls without atherosclerotic lesions, the expression of CD36 was hardly observed, whereas that of SRA was detected weakly but consistently. In contrast, in atherosclerotic lesions, macrophages around the core region showed a weak immunoreactivity to CD36 and a strong immunoreactivity to SRA. Furthermore, lipid-laden macrophages, which mainly existed in the core region, had a strongly positive immunoreactivity to CD36, but a low or moderate level of immunoreactivity to SRA. The distributions of CD36 and SRA were different from each other, and especially foamed, large-sized macrophages in atherosclerotic plaques tended to more abundantly express CD36 protein. These data demonstrate, for the first time, that the expression of both CD36 and SRA might be differentially regulated in aortic walls, and might play different roles in the formation of foam cells in atherosclerotic lesions.

Background Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) is a newly identified member of the EGF family. Our previous in vitro studies showed that HB-EGF is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs), suggesting the role of HB-EGF in the pathogenesis of atherosclerosis. The purposes of the present study were to investigate the localization of HB-EGF in both normal and atherosclerotic human coronary arteries and to elucidate the possible roles of this growth factor in the formation of atherosclerotic lesions. Methods and Results The immunohistochemical localization of HB-EGF, SMCs, macrophages, and EGF receptors (EGFRs) was examined in human coronary arteries obtained at autopsy. The medial SMCs of coronary arteries in neonates, infants, and children consistently synthesized HB-EGF protein. In normal adults, however, the relative number of HB-EGF–positive medial SMCs decreased gradually with age after about 30 years of age. In nonatherosclerotic coronary arteries with diffuse intimal thickening, SMCs of the intima, especially those located in the area of the medial side of the intima, were strongly positive for HB-EGF protein. In atherosclerotic plaques of coronary arteries with eccentric intimal thickening, both SMCs and macrophages in and around the core lesions, in addition to the intimal and medial SMCs located adjacent to the plaque, produced HB-EGF protein. A strong immunostaining of EGFRs was observed in these SMCs, suggesting a close association of HB-EGF and EGFR expression. Conclusions These data suggest that HB-EGF might play important roles in the migration of SMCs from the media to the intima, the proliferation of intimal SMCs, and the interaction between SMCs and macrophages in the process of coronary atherogenesis.

We investigated the acute-phrase and chronic-phase outcomes of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with or without antecedent mutant tissue-type plasminogen (t-PA) administration.Thirty-nine patients with a first AMI within 6 hours of onset were randomly assigned to the treatment group (1,600,000 IU IV monteplase, n = 19) or the nontreatment group (n = 20), followed by PCI. Clinical outcomes were then evaluated.Patient characteristics did not differ between the 2 groups. A significantly higher number of patients in the monteplase group achieved Thrombolysis In Myocardial Infarction trial (TIMI) grade 2 flow or more at the first angiography (84.2% vs 40.0%; P.005), reduced number of devices (1.44 vs 1.80 devices, P.05), and reduced procedure times (59.7 vs 86.7 minutes; P.01), with no differences in peak creatine kinase and rates of major complications and no reflow or distal embolization. Observation over an average of 5.5 months revealed a tendency toward lower target lesion revascularization rates in the monteplase group (17.6% vs 31.6%) but no intergroup difference in rates of major complications. Pretreatment quantitative coronary angioplasty only showed a significant difference in minimal lumen diameter and percent diameter stenosis in the acute phase (1.13 mm in the monteplase group vs 0.66 mm in the nontreatment group, 57.0% vs 73.0%; P.05). (99m)Tc-QGS (quantitative electrocardiographically gated single-photon emission computed tomographic scintigraphy) showed no intergroup differences in left ventricular end-diastolic volume index, end- systolic volume index, and ejection fraction in the acute and chronic phases.Our results suggest that PCI with antecedent mutant t-PA for AMI not only accelerates reperfusion, thereby facilitating PCI, but also attenuates restenosis in the chronic phase.