Masumi Shimizu

Possible participation of Fas-mediated apoptosis in the mechanism of atherosclerosis

Apoptosis is a programmed cell death that plays a major role during development, homeostasis, and in many diseases. Recent evidence has demonstrated the death of vascular smooth muscle cells (VSMCs) within advanced human atheroma. In the rat balloon-injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). To clarify the mechanisms that trigger apoptosis in atherosclerotic lesions, we examined whether cytokines released from macrophages can modulate Fas, a death signal, in cultured human VSMCs. Simultaneous treatment with interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) but not with each cytokine alone induced upregulation of Fas in VSMCs. However, coincubation with NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Fas induced by IL-1 and TNF-alpha. Incubation with sodium nitroprusside, a NO donor, also induced upregulation of Fas in VSMCs. Furthermore, fluorescent nuclear staining with Hoechst 33258 revealed that monoclonal antibody to human Fas significantly enhanced NO-induced apoptotis in VSMCs. These findings suggest that macrophage-derived cytokines can induce upregulation of Fas through a NO-dependent mechanism in VSMCs. Thus, Fas-mediated apoptosis may regulate apoptotic death of VSMCs during atherogenesis.

Increased Plasma Levels of the Soluble Form of Fas Ligand in Patients With Acute Myocardial Infarction and Unstable Angina Pectoris

OBJECTIVES To examine whether the Fas/Fas ligand system is involved in the pathogenesis of acute myocardial infarction (AMI), we measured the levels of the soluble form of the Fas ligand (sFasL) in the plasma of patients with AMI and stable or unstable angina pectoris (AP). BACKGROUND The Fas ligand (FasL) is rapidly cleaved off by a metalloproteinase from the cell membrane to become a soluble form as a cytokine. Fas is expressed in most cells, including cardiomyocytes, whereas FasL is mainly expressed in inflammatory cells such as macrophages, which are greatly accumulated in unstable plaque. METHODS Thirty patients with AMI, 10 patients with unstable AP, 10 patients with stable AP and 30 control subjects were enrolled in the present study. RESULTS Plasma sFasL levels were significantly elevated on hospital admission in patients with AMI and unstable AP, compared with control subjects. Time-course studies revealed that plasma sFasL levels rapidly decreased within 3 h and then increased again after percutaneous transluminal coronary angioplasty in patients with AMI, but not in patients with stable AP. Importantly, the sFasL levels were higher in the coronary sinus than in the circulation. In addition, in vitro studies showed that the expression of FasL messenger ribonucleic acid was upregulated in mononuclear cells isolated from patients with AMI and that hypoxia stimulated the release of sFasL from isolated mononuclear cells. CONCLUSIONS This demonstration of elevated levels of sFasL in patients with AMI and unstable AP suggests that activation of the Fas/FasL system may play a pathogenic role in AMI and acute coronary syndromes.

Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin.

OBJECTIVES We examined whether patients with ischemic heart disease (IHD) should be treated with nicorandil, an adenosine triphosphate-sensitive potassium channel opener, in addition to the regular use of nitrates. BACKGROUND It has been reported that nicorandil possibly has additive effects on nitroglycerin (NTG) treatment for angina, but the mechanism is not clear. METHODS We directly measured anterograde coronary blood flow (CBF) with a Doppler guide wire to examine the effects of intravenous administration of NTG (0.3 mg) and nicorandil (6 mg) during continuous administration of NTG at a sufficient dose (25 microg/min) in subjects with normal and stenotic coronary arteries. RESULTS Additional systemic administration of NTG decreased anterograde CBF (normal -19.7%; stenotic -21.2%). In contrast, nicorandil increased anterograde CBF in both normal (54.6%) and stenotic (89.6%) coronary arteries, without the coronary steal phenomenon. There was a tendency toward nicorandil-dilated diameters in the patients with stenotic arteries (p = 0.06). There were no effects of additional administration on pulmonary artery wedge pressure. There was no difference in changes in heart rate and mean aortic blood pressure between NTG and nicorandil therapy. CONCLUSIONS These results suggest that in patients treated with nitrates, additional administration of nicorandil is more useful, in terms of increasing CBF, than additional administration of nitrates. Adjunctive use of nicorandil with nitrates may provide the further benefit of myocardial protection and may improve the prognosis of patients with IHD.

Interleukin-2 modulates the responsiveness to angiotensin II in cultured vascular smooth muscle cells.

Preincubation with interleukin-2 (IL-2), a T cell-derived cytokine, enhanced the increase in intracellular Ca2+ ([Ca2+]i) induced by angiotensin II (AII) in vascular smooth muscle cells (VSMC). IL-2 itself did not affect the basal [Ca2+]i level or the maximal response of [Ca2+]i increase induced by AII. Furthermore, IL-2-induced enhancement was not observed in the absence of extracellular Ca2+, suggesting that IL-2 enhances Ca2+ influx induced by AII. IL-2 also enhanced the stimulation of DNA synthesis induced by AII, although IL-2 alone did not stimulate DNA synthesis. Genistein, an inhibitor of protein tyrosine kinases, significantly inhibited IL-2-induced enhancement of both Ca2+ influx and DNA synthesis induced by AII. A neutralizing antibody against heparin-binding epidermal growth factor-like growth factor (HB-EGF) partially inhibited IL-2-induced enhancement of DNA synthesis induced by AII. These findings suggest that autocrine HB-EGF is partially involved in the mechanism of IL-2-induced enhancement of DNA synthesis. On the other hand IL-2 stimulated both glycosaminoglycan (GAG) and prostacyclin syntheses and enhanced the stimulation of both GAG and prostacyclin syntheses induced by AII. Therefore, IL-2 may play important roles in the pathogenesis of atherosclerosis and vascular disease by modulating the responsiveness to AII in VSMC.

Endothelin-1 enhances nitric oxide-induced cell death in cultured vascular smooth-muscle cells

Increased expression of endothelin-1 (ET-1) immunoreactivity is demonstrated in the active atherosclerotic plaque. Here we show that both ETA and ETB receptors are expressed in rat vascular smooth-muscle cells (VSMCs). ET-1 binding to ETB receptors enhances nitric oxide-induced cell death in VSMCs. These findings suggest that ET-1 may participate in the mechanism of cell death (apoptosis) in the plaque through activation of ETB-mediated pathways and that a selective ETB receptor antagonist could be useful in preventing acute plaque alterations, such as plaque rupture.

Comparison of effects of estriol on bone mineral density of vertebrae between elderly and postmenopausal women

Abstract: To compare the efficacy of estriol (E3) for postmenopausal and senile osteoporosis, we administered orally 1 g/day calcium lactate alone (control groups) or with 2 mg/day estriol (E3 groups) to 20 postmenopausal women aged 50–65 years and 29 elderly women aged 70–84 years, and determined their bone mineral density (BMD) of the lumbar vertebrae AP scan by dual-energy X-ray absorptiometory. Of 41 subjects who completed 10 months of treatment, 8 postmenopausal women and 12 elderly women in the E3 groups showed a significant (P < .05) increase in BMD, 5.59% ± 4.79% and 3.83% ± 7.90% of the respective basal values, while 10 postmenopausal women and 11 elderly women in the control groups showed a decrease in BMD, −4.02% ± 7.00% and −3.26% ± 4.60% of the respective basal values, after 10 months. On the other hand, genital bleeding as a side effect of E3 occurred in 6 elderly subjects at this dose. Moreover, decrease in serum level of corrected calcium was seen only in the elderly women receiving E3. Although a lower dosage of E3 may be recommended for elderly subjects, these observations suggest, first, that hormone replacement therapy with E3 has efficacy for involutional osteoporosis, and, second, that the bones in elderly women also maintain responsiveness to E3.

Association of angiotensin‐I converting enzyme DD genotype with influenza pneumonia in the elderly

Background: Although angiotensin‐I converting enzyme (ACE) is known to associate with cough reflex and inflammatory conditions, and both may participate in influenza pneumonia in the elderly, no study has been carried out on the association between influenza pneumonia and the insertion/deletion (I/D) polymorphism of the ACE gene (ACE).

TCTAP C-160 The Effective Use of GuideLiner Catheter for Heavily Calcified and Tortuous Just Proximal Left Anterior Descending Intervention

### Patient initials or identifier number 114850 ### Relevant clinical history and physical exam An 87-year-old man admitted to our hospital with effort angina pectoris for one month. He had many risk factors hypertension, dyslipidemia, current smoking, diabetes mellitus, chronic kidney disease,

TCTAP C-062 Guide Wire Fracture in the Coronary Artery and Aorta During Percutaneous Coronary Intervention

### Patient initials or identifier number S.N. ### Relevant clinical history and physical exam A 73 year-old woman was admitted with effort related chest pain for one month. Her coronary risk factors were hypertension, dyslipidemia and chronic obstructive pulmonary disease. The physical