Search

Summary: Unilateral ductuli efferentia testis of immature rat were severed in order to interrupt the continuity between testis and epididymis and angiotensin-converting enzyme (ACE) activities were measured 5 weeks after the operation. The epididymal ACE on the operated side increased to nearly the same level as that on the contralateral side, but the testicular ACE activity on the operated side was markedly lower than that on the contralateral side. On immunofluorescent study using antiserum against purified rat lung ACE, ACE could be found in the tubular epithelial cells of the operated epididymis. These results suggest that epididymis itself synthesize ACE without connection to testis. Zusammenfassung: Die Ductuli efferentes in den Hoden von nicht geschlechtsreifen Ratten wurden einseitig durchtrennt, um die Verbindung zwischen Hoden und Nebenhoden zu unterbrechen. 5 Wochen postoperativ wurde die Aktivitat des Angiotensin-converting-Enzyms (ACE) gemessen. Das ACE im Nebenhoden der operierten Seite stieg annahernd auf das Niveau der kontralateralen Seite, jedoch war die ACE-Aktivitat im Hoden der operierten Seite bedeutend niedriger als auf der kontralateralen Seite. Immunfluores-zenzuntersuchungen mit Antiserum gegen gereinigtes ACE aus Rattenlungen ergab einen Nachweis von ACE in Tubulusepithelzellen des operierten Nebenhodens. Diese Ergebnisse legen nahe, das der Nebenhoden selbst ohne Verbindung zum Hoden ACE synthetisiert.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

A patient with non-Q wave myocardial infarction had severe luminal narrowing in the first major septal perforator branch, which arose anomalously from the first diagonal branch. In this case, an exercise ECG showed a transient leftward QRS axis shift.

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-γ is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-γ gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-δ plays a pivotal role in transactivation of PPAR-γ gene. It has been well known that the interaction between C/EBPs and PPAR-γ plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-γ and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-δ expression induced by inflammation positively regulated transcription and protein expression of PPAR-γ in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-γ ligands troglitazone, pioglitazone, and 15-deoxy-Δ 12,14 -prostaglandin J 2 inhibited IL-1β-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-γ ligands inhibited IL-1β-induced transactivation of IL-6 gene via suppression of not only nuclear factor-κB but also C/EBP-DNA binding. Moreover, PPAR-γ ligands suppressed protein expression and transcription of C/EBP-δ through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-δ is negatively autoregulated via transactivation of PPAR-γ. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

Background— In vitro studies suggest that angiotensin II type 1 and type 2 (AT 1 and AT 2 ) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT 2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT 1a in vascular remodeling. Methods and Results— Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT 1a -null (AT 1a KO), AT 2 -null (AT 2 KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT 2 KO mice, but they were both suppressed in AT 1a KO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT 1a KO mice but decreased in AT 2 KO mice. Reverse transcriptase–polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT 2 KO mice. On the other hand, the expression of bcl-2 and bcl-x L mRNA was enhanced in AT 2 KO mice but attenuated in AT 1a KO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. Conclusions— Our results suggest that AT 2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT 1a in the process of neointimal formation after vascular injury.

Study objectives We sought to assess the incidence of transient U-wave inversion during vasospasm of the left anterior descending coronary artery (LAD) with ST-segment depression as opposed to that with ST-segment elevation. Design Retrospective study. Setting Cardiology division of acute-care hospitals. Patients We studied 49 patients with vasospastic angina whose vasospasm was induced in the LAD, not in the left circumflex coronary artery, by intracoronary injection of acetylcholine. Measurements and results The ECG traces obtained during acetylcholine-induced vasospasm of the LAD were examined. Based on the direction of ST-segment shift, the patients were categorized into two groups: the ST-segment elevation group (n = 27) and the depression group (n = 22). There were no differences in age, gender, or cardiovascular risk factors between the two groups. The distribution of the spastic site in the LAD was also similar. A total reduction in luminal diameter during a provoked attack was more often observed in the ST-segment elevation group than in the ST-segment depression group (37% vs 9%, p = 0.02). Collateral circulation to the LAD was found in only one patient in each group. There were no differences between the two groups in heart rate, systolic BP, and double product of heart rate and systolic BP during the attack. The incidence of acetylcholine-induced anginal attack with U-wave inversion in the ST-segment depression group was nearly as high as that in the ST-segment elevation group (77% vs 78%, p > 0.99). Conclusions The development of transient U-wave inversion during vasospasm of the LAD induced by intracoronary injection of acetylcholine does not depend on the magnitude of myocardial ischemia as judged by the direction of ST-segment shift.

Background The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis. Objective To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients. Patients and main outcome measures Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay. Results Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030). Conclusions These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.

Eosinophilic pleural effusion occurs in many diseases. The mechanisms of eosinophil accumulation are not well understood. We showed previously that eotaxin was readily detectable in most pleural effusions, and its concentration significantly correlated with eosinophil number. To test the hypothesis that pleural eotaxin is produced by resident mesothelial cells, we examined its production by normal pleural mesothelial cells (NPMC). Eotaxin was induced by tumor necrosis factor (TNF)-alpha or interleukin (IL)-4 and was drastically increased by their combination. In contrast, interferon (IFN)-gamma inhibited eotaxin production. Regulated on activation, normal T cells expressed and secreted (RANTES) was also induced by TNF-alpha and was drastically increased by the addition of IFN-gamma. These effects were observed at both protein and mRNA levels. Stabilization of RANTES mRNA was observed with IFN-gamma but not IL-4; neither cytokine stabilized eotaxin mRNA. Eosinophil chemoattractant activity in culture supernatants of NPMC stimulated with TNF-alpha plus IL-4 was diminished by an anti-eotaxin antibody; that induced by TNF-alpha plus IFN-gamma was attenuated by an anti-RANTES antibody. Thus, NPMC can produce eotaxin, and different cytokines act on NPMC to induce different chemokines by different mechanisms. IFN-gamma, a Th1 cytokine, acts at least at the posttranscriptional level to induce RANTES production, but it inhibits eotaxin production. In contrast, IL-4, a Th2 cytokine, acts at the transcriptional level to induce eotaxin.

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3–7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

Serum response factor and the (CC(A/T)(6)GG) (CArG) box interact to promote the transcription of c-fos and muscle genes; this tissue-specific activity may require co-regulators for serum response factor. The alpha(1) integrin promoter contains two cis-elements besides the CArG box: a TAAT sequence, a consensus binding site for homeoproteins, and a GATA-binding box. As a candidate TAAT-binding factor, we cloned an NK family homeobox gene, Nkx-3.2, which is expressed mainly in smooth muscle tissues and skeletal structures. Nkx-3.2, serum response factor, and GATA-6 were co-expressed only in the medial smooth muscle layer of arteries. These three transcription factors formed a complex with their corresponding cis-elements and cooperatively transactivated smooth muscle genes, including alpha(1) integrin, SM22alpha, and caldesmon. Cardiac muscle-specific members of the NK and GATA families exist, and the triad of Nkx-2.5, serum response factor, and GATA-4 also transactivated the cardiac atrial natriuretic factor gene, which contains a CArG-like box, a GATA-binding box, and an NK-binding element. Our findings demonstrate that smooth and cardiac muscle have a shared transcriptional machinery and that the GATA and NK families confer muscle specificity on the serum response factor/CArG interaction.

The exact mechanisms responsible for the progression of heart failure remain unclear. We investigated the in vivo relationship between the incidence of apoptotic cell death and left ventricular function serially from the beginning of hypertension to decompensated heart failure in Dahl salt-sensitive rats. Dahl salt-resistant and Dahl salt-sensitive rats were fed on a high-salt diet from 6 weeks of age. Systolic blood pressure was recorded by the tail-cuff method every week. Cardiac function in vivo was evaluated by echocardiography and cardiac catheterization. Cardiomyocyte apoptosis was detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) method. The gene expression of Bax, Bcl-2 and Bcl-xL was analysed by Northern blotting. The TUNEL method revealed that the incidence of cardiomyocyte apoptosis was significantly increased in the hearts of 18-week-old Dahl salt-sensitive rats (apoptotic index 1.3±0.1%). Northern blot analysis revealed that the Bcl-xL mRNA level increased gradually during the progression towards heart failure. In conclusion, these data suggest that cardiomyocyte apoptosis is a terminal event, and plays a role as an aggravating factor in the vicious cycle of heart failure.

KL-6, surfactant protein (SP)-A, SP-D, and monocyte chemoattractant protein-1 (MCP-1) are reported to be sensitive markers for interstitial lung diseases (ILD). However, each marker has been studied independently. The aim of this study was a comparative analysis of the diagnostic values of these markers. Subjects consisted of 33 patients with ILD (21 cases of idiopathic pulmonary fibrosis and 12 associated with collagen vascular diseases) and 82 control subjects (12 cases of bacterial pneumonia and 70 healthy volunteers). Receiver operating characteristic curves revealed that KL-6 was superior to the other markers. The cut-off levels for these markers that resulted in the highest diagnostic accuracy were determined to be 465 U/ml for KL-6, 48.2 ng/ml for SP-A, 116 ng/ml for SP-D, and 1080 pg/ml for MCP-1. The sensitivity, specificity, and diagnostic accuracy were 93.9%, 96.3%, and 95.7% for KL-6; 81.8%, 86.6%, and 85.2% for SP-A; 69.7%, 95.1%, and 87.8% for SP-D; and 51.5%, 92.7%, and 80.9% for MCP-1; respectively. The serum levels of SP-A and SP-D, but not of KL-6, were significantly higher in patients with bacterial pneumonia than in healthy volunteers. These results suggest that of the markers studied, KL-6 is the best serum marker for ILD.

Insulin-like growth factor-1 (IGF-1) is important in the hypertrophic response of the myocardium, so the present study was designed to elucidate whether the circulating levels of IGF-1 and its binding proteins (IGFBPs) are related to the disease condition of patients with hypertrophic cardiomyopathy (HCM), in particular the occurrence of congestive heart failure (CHF). The study group comprised 124 patients with HCM and 15 healthy control subjects. The HCM patients were subdivided into 3 groups: 39 with hypertrophic obstructive cardiomyopathy (HOCM), 67 with hypertrophic non-obstructive cardiomyopathy (HNCM), and 18 with HCM and a history of CHF (HF-HCM, n=18). Serum levels of IGF-1 and IGFBPs (IGFBP-1 and -3) were compared between groups. IGF-1 levels were significantly higher in patients with HOCM and HNCM, and lower in patients with HF-HCM than in control subjects (p

A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines. (Hypertens Res 2002; 25: 69-75)

To evaluate the aortic wall distensibility (AD) in hemodialysis patients, we measured AD at the ascending aorta using cine magnetic resonance imaging in 10 hemodialysis patients (HDP) and 10 normal controls (NC). Age and sex were matched in HDP and NC. Transverse image of the aorta was measured in the maximum and minimum frames. AD was calculated from the following formula: (Max. area — Min. area)/Min. area × pulse pressure). Although systolic blood pressure, diastolic blood pressure, and minimum area of ascending aorta showed no significant differences between HDP and NC, AD was significantly lower in HDP (2.95±0.87 × 10−3 mmHg−1) than in NC (6.61±3.12×10−3 mmHg−1) (p

Tropomyosin (TM) is a regulatory protein of actomyosin system. Muscle type-specific expression of TM isoforms is generated from different genes and by alternative splicing. beta-TM isoforms in chicken skeletal and smooth muscles are encoded by a single gene and transcribed from the same promoter. We previously reported a smooth muscle cell (SMC) phenotype-dependent change in beta-TM expression (Kashiwada, K., Nishida, W., Hayashi, K., Ozawa, K., Yamanaka, Y., Saga, H., Yamashita, T., Tohyama, M., Shimada, S., Sato, K., and Sobue, K. (1997) J. Biol. Chem. 272, 15396-15404), and identified beta-TM as an SMC-differentiation marker. Here, we characterized the transcriptional machinery of the beta-TM gene in SMCs. Promoter and gel mobility shift analyses revealed an obligatory role for serum response factor and its interaction with the CArG box sequence in the SMC-specific transcription of the beta-TM gene in differentiated SMCs. We further isolated a novel homologue of the Barx homeoprotein family, Barx1b, from chicken gizzard. Barx1b was exclusively localized to SMCs of the upper digestive organs and their attached arteries and to craniofacial structures. Serum response factor and Barx1b bound each other directly, coordinately transactivated the beta-TM gene in differentiated SMCs and heterologous cells, and formed a ternary complex with a CArG probe. Taken together, these results suggest that SRF and Barx1b are coordinately involved in the SMC-specific transcription of the beta-TM gene in the upper digestive organs and their attached arteries.

CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGFalphaR). Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs). In the present study, we clarified a functional relationship between C/EBPs and PPARgamma in the regulation of IL-1beta-induced PDGFalphaR expression in VSMCs. PPARgamma activators, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2), inhibited IL-1beta-induced PDGFalphaR expression and suppressed PDGF-induced proliferation activity of VSMCs. Electromobility shift and supershift assays for a C/EBP motif in the PDGFalphaR promoter region revealed that PPARgamma activators suppressed IL-1beta-induced DNA binding activity of C/EBPdelta and beta. PPARgamma activators also suppressed IL-1beta-induced C/EBPdelta expression. In contrast, overexpression of C/EBPdelta reversed the suppressive effect of PPARgamma activators on PDGFalphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPARgamma activators on PDGFalphaR expression is mainly mediated by C/EBPdelta suppression. Regulation of C/EBPdelta by PPARgamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.

Growth arrest and DNA damage inducible gene 153 ( gadd153 ) is expressed at very low levels in growing cells but is markedly induced in response to cellular stresses, including glucose deprivation, exposure to genotoxic agents, and other growth-arresting situations. Forced expression of GADD153 can induce cell cycle arrest and/or apoptosis in many types of cells. Recently, we reported that GADD153 was induced in vascular smooth muscle cells (VSMCs) in neointimal lesions of balloon-injured carotid arteries. To investigate the underlying molecular mechanisms of gadd153 gene expression in VSMCs, we isolated and characterized a promoter region of the rat gadd153 gene. Sequence alignments of this region revealed 1 TATA-like sequence and several well-known cis elements. The 5′-deletion analysis for this region showed that a domain spanning −447 through −368 drastically reduced the promoter activity to almost equal levels of promoterless control. Because this domain contained a consensus sequence for the nuclear factor 1 family of proteins (NF1), DNA-binding studies were performed by use of 2 types of NF1 consensus probes. Both probes were specifically shifted by nuclear extracts from proliferating VSMCs and were supershifted by antiserum against CCAAT transcription factor/NF1. In addition, promoter activity of a mutant luciferase vector, which was generated by a point mutation at the NF1 binding motif of the gadd153 gene, was 14-fold higher than that of a wild-type one. These results suggest that gadd153 gene expression in VSMCs is negatively regulated by an NF1-binding motif, and NF1 may act as an antiapoptotic factor by continuously suppressing gadd153 gene expression in growing VSMCs.

Background: In naive rodents, repeated exposure to aerosolized antigen induces suppression of the Th2 response to the antigen. We hypothesized that more prolonged exposure of established asthma model to antigen aerosols may downregulate asthmatic phenotype. Methods: After establishing an ovalbumin (OVA)-induced asthma model, mice were further exposed to OVA (prolonged exposure group) or phosphate-buffered saline (positive controls) 3 days per week for 6 weeks. During week 7, the mice of both groups were finally challenged with OVA. Results: Prolonged OVA exposure resulted in marked suppression of serum OVA-specific immunoglobulin E (IgE) antibody levels, eosinophilia of the airway, and airway hyperresponsiveness (AHR). However, airway remodeling characterized by goblet cell hyperplasia and airway fibrosis was observed to the same degree in both groups. These effects were accompanied by diminished production of Th2 cytokines such as interleukin-4 (IL-4), IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) and cultured supernatant of splenocytes. Furthermore, prolonged exposure markedly increased IL-12 levels in BALF. Conclusions: Prolonged antigen exposure has inhibitory effects on eosinophilic inflammation, AHR and IgE response to antigen, but not on airway remodeling, presumably via inhibition of Th2 cytokines and increased IL-12 production in the lungs.

The effect of cibenzoline on left ventricular diastolic function was investigated in patients with hypertrophic cardiomyopathy (HCM). Before and 2 h after an oral administration of 200 mg of cibenzoline, echocardiographic, apexcardiographic and gated radionuclide angiographic studies were performed in 12 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 7 with hypertrophic nonobstructive cardiomyopathy (HNCM). After administration of cibenzoline, the left ventricular pressure gradient decreased from 96+/-33 mmHg to 29+/-22 mmHg (

A 65-year-old Japanese woman was admitted to hospital because of exertional dyspnea. Transthoracic echocardiography showed diffuse hypokinesis of the left-sided ventricular wall, but was not clear enough to provide useful information because of the rotation of the cardiac apex and the presence of lung tissue. Systemic ventriculography showed that the left-sided ventricle with heavy trabeculations was morphologically similar to a normal right ventricle. Magnetic resonance imaging (MRI) clearly revealed corrected transposition of the great arteries. Because this patient had no severe associated cardiac anomalies, systemic ventricular dysfunction is thought to be the major cause of exertional dyspnea. MRI is a useful non-invasive method for the rapid evaluation of cardiac morphology.

A 65-year-old Japanese woman with dilated cardiomyopathy, hypothyroidism and refractory sustained ventricular tachycardia experienced a near-death hypoglycemic syncope. The attack seemed to be induced by a high level of serum insulin, probably due to cibenzoline and by concomitant use of an angiotensin converting enzyme inhibitor (ACEI). Additionally, decreased food intake because of a severe toothache may have contributed to the deterioration of her condition. This case warns cardiologists that a combined cibenzoline and ACEI therapy can provoke serious adverse effects such as hypoglycemic syncope in the elderly. Therefore, the possibility of a hypoglycemic attack associated with these drugs should be explained to patients who are in poor condition.

A 65-year-old man with sarcoidosis, accompanied by muscle nodules, noticed a painless and enlarged nodule in his forearm. MRI of the nodule showed that a star-shaped area of lower signal intensity was surrounded by an area of higher signal intensity. Histological examination showed granulomas composed of multinuclear giant cells and epithelioid cells. Sarcoidosis was diagnosed. Eight months later, he was admitted to our hospital because of enlargement of the nodular region with pain and stiffness. Marked uptake of 67Ga was observed in the right arm and leg. MRI revealed sarcoid nodules in these regions. An enlargement of the higher signal intensity area was observed in the right forearm nodule. We started administration of prednisolone. Forty days later, his symptoms had disappeared and the size of higher signal intensity area of the nodule had reduced dramatically. 67Ga scintigram and MRI were useful for diagnosis and monitoring during therapy in this patient.

Myasthenia gravis (MG) is characterized by weakness of skeletal muscles because of a decrease in the number of available acetylcholine receptors at neuromuscular junctions. Anticholinesterase medication is widely used to treat MG, but muscarinic side effects sometimes appear and limit the drug usage. To their knowledge, the authors present the first case of coronary spastic angina quite possibly induced by anticholinesterase medica tion to treat MG. The appearance of coronary spastic angina in the present case is likely mediated through the increase of acethylcholine by anticholinesterase medication.

Thiazolidinediones, activators of peroxisome proliferator-activated receptor (PPAR)gamma, have been reported to induce apoptosis in many types of cells. In the present study, we investigated the effects of thiazolidinediones, troglitazone, and pioglitazone on the cell growth of vascular smooth muscle cells, and identified a specific effect of troglitazone in addition to PPARgamma activation. Subconfluent rat culture vascular smooth muscle cells were treated with or without PPARgamma activators, troglitazone (1-30 microM), or pioglitazone (1-30 microM) for 72 h. After treatment, cell viability was significantly reduced by troglitazone in concentrations of 5-30 microM but not by pioglitazone. Vascular smooth muscle cells appeared to float and shrink 48 h after treatment with 20 microM of troglitazone. In situ DNA labeling showed that the nuclei of these cells were positively stained, and genomic DNA extracted from the cells showed nucleosomal laddering. Messenger RNA expression levels of c-myc, p21, bax, bcl-2, and bcl-x were not changed by the treatment with troglitazone. In contrast, along with the induction of vascular smooth muscle cell apoptosis, both the mRNA and protein expression levels of p53 and Gadd45 markedly increased in response to troglitazone. These results strongly suggest that troglitazone can induce vascular smooth muscle cell apoptosis and that this effect is caused primarily by activation of the p53 and Gadd45 pathway but not by PPARgamma activation.

Background and Purpose —Mechanical stresses on the arterial wall participate in the pathogenesis of atherosclerosis as local factors. The relationships between local mechanical forces and risk factors for atherosclerosis were investigated. Methods —Mechanical forces on the arterial wall were evaluated in the carotid artery in 117 patients with risk factors for atherosclerosis including hypertension, dyslipidemia, diabetes mellitus, and smoking, as well as in 20 age- and sex-matched normal controls. Circumferential wall tension and shear stress were evaluated with Laplace’s law and a poiseuillean parabolic model of velocity distribution. Circumferential wall strain was also evaluated as carotid mechanical force. Results —Mechanical forces in subjects with risk factors were characterized by low wall shear stress, high circumferential wall tension, and reduced strain. Systolic blood pressure was significantly negatively associated with shear stress and circumferential wall strain. HDL cholesterol showed a significant positive correlation with shear stress and a negative correlation with wall tension. Fasting blood glucose was significantly associated with shear stress, while smoking showed a negative correlation with shear stress and a positive correlation with wall tension. Accumulation of risk factors was associated with further deterioration of mechanical forces. Furthermore, stepwise regression analysis showed that the number of risk factors was significantly associated with mechanical forces independently of carotid intima-media thickness. Conclusions —These findings suggest that risk factors for atherosclerosis were associated with alteration of mechanical forces. Consequent alteration in mechanical forces could be an underlying local mechanism for the progression of atherosclerosis.

A 25-year-old man with low cardiac risks underwent coronary arteriography because of chest pain at rest. His only risk factors for coronary artery disease was smoking. Both right and left coronary arteries were ectatic and the left anterior descending artery was obstructed. In the acetylcholine provocation test, the left circumflex coronary artery showed severe constriction. Thus, this patient was diagnosed as having a combination of variant angina and occlusive coronary artery disease.

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular complications including atherosclerosis. The close linkage between LVH and carotid atherosclerosis has been the focus of much research. However, the underlying mechanism linking the two conditions is not fully understood. Low wall shear stress contributes to intimal thickening and atherosclerosis development as a local mechanism. In the present study, we investigated the relationship between wall shear stress and LVH in subjects with risk factors for atherosclerosis. Eighty subjects with at least one risk factor for atherosclerosis; ie, hypertension, diabetes mellitus, hyperlipidemia, or smoking, were enrolled. Intimal-medial thickness (IMT), number of plaques, internal dimensions, and blood flow velocity in the common carotid artery were evaluated. Wall shear stress was calculated using a Poiseuillean parabolic model of velocity distribution: shear stress = 4 x blood viscosity x central flow velocity/internal dimension. Subjects were divided into two groups; LVH(-) (n = 36) and LVH(+) (n = 44), according to their left ventricular mass index (LVMI). Mean shear stress and systolic peak shear stress were significantly lower in subjects with LVH compared with subjects without LVH. Furthermore, mean shear stress (r = -0.42, P < .0001) and peak shear stress (r = -0.31, P < 0.01) were significantly inversely related to LVMI. Stepwise regression analysis revealed that wall shear stress independently correlated with LVMI as well as IMT. These results indicate that low shear stress could function as a local factor in the development of atherosclerosis in subjects with LVH.

The transient U wave inversion during exercise is specific for detecting left anterior descending coronary artery (LAD) disease. In a homogeneous patient group restricted to LAD disease, however, the significance of the electrocardiographic finding has not yet been clarified. Thus, clinical characteristics in patients with angiographically documented one-vessel disease of the LAD and exercise-induced U wave inversion were delineated. Symptom-limited treadmill exercise testing was performed in 60 patients (43 men, 17 women; mean age 64 ±8 years) with angina pectoris whose culprit lesion was located only in the LAD. U wave polarity and amplitude were determined before, during, and after exercise with the P-Q segment as the isoelectric line. Exercise-induced transient U wave inversion was defined as positive when there was a discrete negative deflection ≥ 0.05 mV within the T-P segment. Of all patients, 16 (27%) had exercise-induced U ( continued on next page) wave inversion. There were no differences in age, male gender, antianginal medication use, and coronary angiographic data between the two patients groups: patients with and without U wave inversion. Heart rate and double product of heart rate and systemic systolic blood pressure at peak exercise were also similar. Prevalence of abnormal exercise-induced S-T segment shift was 94% (15 of 16 patients) and 61% (27 of 44 patients) of patients with and without U wave inversion, respectively. The difference was statistically significant (p = 0.02). Among patients with exercise-induced S-T segment shift, the proportion of patients with S-T segment elevation to all the patients was larger in patients with U wave inversion than in patients without U wave inversion [3 (20%) of 15 patients vs 0 (0%) of 27 patients, p=0.03)]. In conclusion, the exercise-induced U wave inversion in patients with one-vessel disease of the LAD indicates the severe degree of myocardial ischemia induced in the territory perfused by the LAD. However, the elec trocardiographic finding does not appear to have independent significance since it closely correlates with the presence of S-T segment shift.

To examine whether plasma levels of brain natriuretic peptide identify hypertensive patients at risk for progressive cardiac hypertrophy.We examined the association between plasma brain natriuretic peptide levels and left ventricular structural changes in 54 hypertensive patients and 28 normotensive control subjects. Patients were divided into those with elevated (n = 14) or normal (n = 40) levels of brain natriuretic peptide, based on a cutoff level of 41 pg/mL (2 SD above the mean in the control subjects). Left ventricular function and geometry were assessed echocardiographically at baseline and follow-up.At baseline, initial left ventricular chamber size, wall thickness, and systolic function did not differ between the hypertensive patients and normotensive subjects. After a mean (+/- SD) follow-up of 9 +/- 3 months, blood pressure was relatively unchanged in the hypertensive patients with normal brain natriuretic peptide levels, whereas there were significant increases in systolic blood pressure and pulse pressure (both P0.05 versus baseline) in patients with elevated brain natriuretic peptide levels. Moreover, left ventricular midwall systolic function had decreased significantly at follow-up in those with elevated levels (P0.05 versus baseline). At follow-up, the hypertensive patients with elevated brain natriuretic peptide levels had a significantly greater left ventricular mass index and relative wall thickness than those with normal levels. Multiple regression analyses determined that only initial plasma brain natriuretic peptide was significantly (P0.01) associated with subsequent left ventricular hypertrophy.Plasma brain natriuretic peptide levels may identify hypertensive patients who are likely to have progressive cardiac hypertrophy.

Background There has been no report of ECG changes during anginal attacks in patients with coexistent hypertrophic cardiomyopathy (HCM) and vasospastic angina. Study objectives To elucidate the change in ST-segment during anginal attacks in patients with coexistent HCM and vasospastic angina (the HCM group) in comparison with that of patients with vasospastic angina and no left ventricular hypertrophy (the non-HCM group). Design Retrospective study. Patients Twelve patients in the HCM group, and 28 patients in the non-HCM group. Measurements The direction of ST segment shift, either ST-segment elevation or depression, on the ECGs recorded during vasospastic anginal attacks with severe vasoconstriction in the epicardial coronary artery after intracoronary injection of acetylcholine. Results Age, male gender, and distribution of coronary arteries in which the vasospasm occurred were similar between the two groups. Collateral circulation to the affected arteries was absent in all the study patients. The prevalence of anginal attacks associated with ST-segment elevation was 2.7 times higher in the non-HCM group than in the HCM group (51.5% [17 of 33 attacks] vs 18.8% [3 of 16 attacks], respectively; p = 0.03). Conclusions In the HCM group, myocardial ischemia associated with a transmural injury pattern seen on the ECG, which is represented as ST-segment elevation, seldom develops during vasospastic anginal attacks because of marked left ventricular hypertrophy.

A great deal of attention has been focused on the antitumor effects of anti-MUC1 humoral and cellular responses. We examined whether anti-MUC1 antibody is present in patients with lung cancer, and evaluated its prognostic value. Serum was obtained from 30 patients with nonresectable, non-small cell lung cancer (NSCLC) and 60 healthy volunteers. The presence of anti-MUC1 antibody was determined by enzyme-linked immunosorbent assay. The patients were observed for a median follow-up time of 54.0 mo. Overall survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed using the Cox proportional hazards regression model. Anti-KL-6/MUC1 antibody levels of the patients were significantly lower than those of normal individuals (p < 0.001). One-year survival rate of patients with high concentrations of anti-KL-6/MUC1 antibody was significantly higher than that of patients with low levels of anti-KL-6/MUC1 antibody (90.9% versus 21.1%, p < 0.001). Anti-KL-6/MUC1 antibody status was most strongly correlated with mortality, followed by lymph node status and albumin levels, whereas sex, serum lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA) levels, and metastasis status did not correlate with mortality. These preliminary results indicate that the degree of decrease in antibody level may be associated with a patient's prognosis.

A 58-year-old male patient had apical hypertrophic cardiomyopathy (HCM) associated with a life-threatening tachycardia due to atrial flutter. Following palpitation and dyspnea for 2-3 h, he became unconscious because of circulatory catastrophe, but was fully resuscitated. An electrocardiogram recorded just before the loss of consciousness revealed atrial flutter at a rate of 260 beats/min with a 2:1 ventricular response. He was diagnosed as having apical HCM based on the echocardiographic and left ventriculographic findings. Atrial stimulation at a rate of 150 pacings/min for 1 min caused a marked drop in systemic systolic blood pressure from 170 to 120 mmHg. The patient was treated with 150 mg of cibenzoline per day to prevent supraventricular tachyarrhythmias and to improve left ventricular diastolic function. At the time of the recent follow-up at 2 and a half years, he felt quite well.

To evaluate whether or not beta-blockers can improve the condition of patients with heart failure treated with a combination of diuretics, digitalis and angiotensin-converting enzyme inhibitor (ACEI), 52 patients with chronic heart failure who have been treated with ACEI for more than 6 months were enrolled. They were divided into 2 groups: 26 patients continued the same therapy another 6 months or more (group A), and 26 patients were given oral metoprolol for 6 months or more, in addition to the ACEI (group B). Echocardiographic parameters and atrial and brain natriuretic peptides (ANP, BNP) were measured. The left ventricular dimensions at end-diastole and end-systole were significantly decreased and fractional shortening was significantly increased in group B after 6 months' treatment with the beta-blocker, but these parameters remained unchanged in group A. Plasma levels of both ANP and BNP were significantly decreased in group B, but remained unchanged in group A. These results indicate that concomitant beta-blocker therapy can improve left ventricular function and attenuate plasma ANP and BNP levels in patients with chronic heart failure treated with ACEI.

Serial changes of left ventricular (LV) geometry and function during the development of hypertension were studied in 50 Dahl salt-resistant (DR) and 88 Dahl salt-sensitive (DS) rats fed an 8% NaCl diet beginning at the age of 6 weeks. Echocardiography at 6, 8, 11, 13, 14, 15, and 18 weeks and in vivo invasive hemodynamic determination at 6, 8, 11, 14, and 18 weeks were performed. After 11 weeks, 33 DS rats were observed for survival analysis. The survival analyses showed that the incidence of death was 57.6% due to heart failure, 27.3% due to stroke, and 15.2% due to sudden death. However, death in the early stages of hypertension was due almost entirely to sudden death or stroke. A high value of relative wall thickness (RWT) and a small end-diastolic dimension were predictive of sudden death and stroke, but LV mass (LVM) was not. Concerning the change in LV geometric patterns, LVM continued to increase to 18 weeks. The RWT increased or remained at a plateau up to 13 weeks, and then progressively decreased after 13 weeks. In contrast, LV function was hyperdynamic between 8 and 11 weeks when compared to DR rats. However, after 13 weeks, all hemodynamic variables of DS rats deteriorated progressively, and all DS rats died of heart failure. Thus, our study indicates that the cardiovascular events associated with the progression of hypertension vary widely according to the stage of hypertension and that RWT is more sensitive in predicting LV conditions than LVM in hypertension.

We reported on a 79-year-old woman with pneumonia caused by Mycobacterium avium complex (MAC). She was admitted with fever, general fatigue, and cough. A chest X-ray film showed infiltrative shadows in the right lung field. In spite of administration of conventional antibiotics, the infiltrative shadows enlarged. A chest CT scan revealed areas of consolidation and ground glass opacities. Bronchoalveolar lavage (BAL) examination revealed an increased number of lymphocytes. Transbronchial lung biopsy revealed many granulomatous regions with giant cells. Mycobacterium intracellulare was found in the culture of BAL fluid and identified by PCR. Treatment was started with rifampicin, ethambutol, and clarithromycin. However, rifampicin and ethambutol were soon discontinued because of severe anorexia. Her symptoms and the radiographic appearance markedly improved following treatment of clarithromycin alone. Subsequently small doses of rifampicin and ethambutol were restarted because her general condition was much improved. These findings suggest that clarithromycin is an effective and tolerable agent for elderly patients with MAC.

Background: Docosahexaenoic acid (DHA) found in fish oil is known to depress inflammation-related mediators. We investigated a novel delivery method of tridocosahexaenoyl-glycerol (DHA-TG). Methods: BALB/c mice (6–8 weeks old) were primed intraperitoneally with ovalbumin (OVA) and Al(OH)3 on days 0 and 7, and with aerosolized OVA on day 7. Primed mice were challenged by repeated exposure to aerosolized OVA on days 15–17. Just before each exposure to aerosolized OVA, the mice were also exposed to an aerosol of emulsified DHA-TG or soybean oil, or saline (days 7 and 15–17). Bronchial hyperresponsiveness (BHR) to methacholine was measured, and bronchoalveolar lavage fluid was obtained 24 h after the last challenge (day 18). Lungs were histologically examined. Results: Bronchoalveolar lavage fluid of saline-treated mice showed an increased cellularity with predominant eosinophils. Exposure to DHA-TG significantly reduced the total cell number and the eosinophil percentage in lavage fluid, whereas soybean oil did not. Conclusion: DHA but not soybean oil exposure reduced BHR and cell infiltration to bronchovascular bundles. This type of DHA administration could be studied in clinical trials.

To elucidate the mechanism of left ventricular dysfunction associated with left ventricular hypertrophy in hypertension, coronary blood flow (CBF) and left ventricular mass (LVM) were measured in 62 patients with essential hypertension (mean age, 54±13 years) and 22 normotensive control subjects (mean age, 57 ±13 years). According to the indicator fractionation principle, CBF/cardiac output (CO), estimated on the basis of the ratio of myocardial uptake/total injected dose of thallium-201 (% cardiac uptake), was measured. CBF and CBF per 100g of myocardium (unit CBF) were calculated according to the following formulas: CBF=% cardiac uptake×CO, and unit CBF=(CBF/LVM)×100, where CO and LVM are echocardiographically determined. Midwall fractional shortening (FS) and isovolumic relaxation time (IRT) were calculated as the indices of systolic and diastolic functions. CBF was greater in hypertensives than in controls (218.2±74.0 vs. 187.4±40.4ml/min, p

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced (P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.

An asymptomatic 88-year-old woman underwent a screening medical examination. The chest x-ray film showed a large mediastinal mass with calcification. Both chest computed tomography and nuclear magnetic resonance imaging revealed an unruptured aortic aneurysm, predominantly affecting the ascending aorta and the proximal part of the aortic arch. Its maximum diameter was 10.5 cm. An ascending aortic aneurysm more than 10 cm in diameter is very rare. She died of acute pulmonary embolism unrelated to the aneurysm, and autopsy indicated that the etiology of the aneurysm was atheroscle rotic degeneration. Retrospectively, the natural progression of the aneurysm was able to be followed on a series of chest x-ray films obtained over 18 years.

Pressure wave reflection plays a pivotal role in the augmentation of systolic blood pressure. In the present study, the association between reflection of pressure wave and structural and functional alteration, including blood flow, in the common carotid artery was investigated in 70 hospitalized essential hypertensive patients. The reflection of pressure was estimated by the “augmentation index” of the carotid arterial pressure waveform. The carotid augmentation index was significantly related to age (r = 0.36), body height (r = −0.30), intima-media thickening (r = 0.28), number of plaques (r = 0.44), stiffness of the carotid artery (r = 0.38), diastolic carotid flow velocity (r = −0.31), and left ventricular mass index (r = 0.33). Furthermore, the reflection of arterial pressure showed a significant negative correlation with diastolic/systolic ratio of blood flow velocity in the carotid artery (r = −0.41, P = .0005). Stepwise regression analysis revealed that age and left ventricular mass index were independent determinants for the carotid augmentation index. These findings indicate that the reflection of arterial pressure is related to morphological and functional alterations of the carotid artery, including a relative reduction of diastolic blood flow.

SUMMARYThe dose of antigen is assumed to be one of the important factors in the polarized development of helper T cell subsets, i.e. Th1 or Th2 cells. We investigated the effect of the sensitizing antigen dose in a murine model of atopic asthma, which involved sensitization with ovalbumin (OVA) followed by repeated exposure to OVA aerosols. BALB/c mice were primed with varying doses of OVA (0, 10, 100 and 1000 μg) plus Al(OH)3 on days 0, 7 and 14, and were challenged with OVA aerosols (50 mg/ml for 20 min) on days 15–20. There were striking antigen dose-related differences in OVA-specific antibodies: high IgE and low IgG2a titres were found in mice sensitized at 10 μg, while low IgE and high IgG2a titres were seen at 1000 μg. The sensitizing dose was inversely correlated with the total cell count and the eosinophil count in bronchoalveolar lavage fluid (BALF), as well as with the extent of histological changes such as goblet cell hyperplasia of the bronchial epithelium and cellular infiltration into bronchovascular bundles. Antigen-induced bronchial hyper-responsiveness (BHR) to methacholine was observed with sensitization at 10 μg but not at 1000 μg. Splenic mononuclear cells (SMNC) obtained from mice sensitized at either dose showed proliferation in response to OVA. Production of IL-4 and IL-5 by OVA-stimulated SMNC was inversely correlated with the dose of sensitizing antigen. High-dose sensitization resulted in general suppression of cytokine production by SMNC, including interferon-gamma (IFN-γ). The BALF levels of IL-4 and IL-5 were increased by low-dose sensitization, whereas IFN-γ and IL-12 levels were increased by high-dose sensitization. These results suggest that the dose of sensitizing antigen defines the phenotypic changes in the present murine asthma model, presumably by influencing the pattern of cytokine production.

In the present study, we evaluated the effect of aging on diurnal change in blood pressure in stroke-prone spontaneously hypertensive rats (SHRSP/Izm) using a telemetry system. Diurnal changes in blood pressure, heart rate, and locomotor activity were determined in unrestrained, freely moving condition in 24-week-old male SHRSP/Izm (n = 6) and 40-week-old male SHRSP/Izm (n = 6). Diurnal change in blood pressure was also investigated in 40-week-old male spontaneously hypertensive rats (SHR/Izm, n = 6) and Wistar-Kyoto rats (WKY/Izm, n = 5) as age-matched controls of the strain. All rats were kept in a 12-h light/dark cycle (light period from 06:00 to 18:00, and dark period from 18:00 to 06:00). Rats were active in dark phase and inactive in light phase. Mean blood pressures (MBP) were significantly higher in light phase as well as dark phase in old SHRSP/Izm compared with the other three groups. Light/dark phase ratio of MBP was significantly higher in old SHRSP/Izm compared with the other three groups. We observed a significant positive relationship between light/dark phase ratio of MBP and left ventricular mass index in a studied population of rats (r = 0.547, P Because SHRSP is a salt-sensitive model, the effect of high salt loading on the circadian pattern of blood pressure was also investigated. Male SHRSP/Izm, at the age of 22 weeks, were maintained on high salt (8%) for 2 weeks. High salt exposure significantly increased dark phase as well as light phase MBP in SHRSP/Izm. However, light/dark phase ratio of MBP was not significantly different from normal salt-fed (0.6%) SHRSP/Izm. These results indicate that aging and end-organ damage were associated with the alteration of diurnal change in blood pressure in SHRSP/Izm.

Various alterations in molecular and cellular events have been considered as possibly contributing to the cardiac remodelling that occurs during the transition from compensated hypertrophy to heart failure. The aim of the present study is to clarify (1) whether cardiac apoptosis occurs during the transition from compensated hypertrophy to decompensated heart failure, and (2) whether expression of the genes encoding Bax (an apoptosis inducer) and Bcl-xL and Bcl-2 (apoptosis inhibitors) is altered during this transition. We used 12-month-old and 20-month-old male spontaneously hypertensive rats (SHR 12 and SHR 20 respectively) and age-matched Wistar–Kyoto rats (WKY 12 and WKY 20 respectively). These rats were killed after measurement of haemodynamic parameters by transthoracic echocardiography and use of a tipmanometer via the right carotid artery. The expression of bcl-2 , bcl-xL and bax was analysed by Northern blotting. Samples were also fixed in 4% paraformaldehyde for in situ nick end-labelling (TUNEL) methods and immunohistochemistry. SHR 12 had well compensated left ventricular hypertrophy with normal fractional shortening and normal end-systolic wall stress. In contrast, the hearts of SHR 20 developed decompensated dilatation, with a decrease in fractional shortening and an increase in end-systolic wall stress. TUNEL-positive cells were seen exclusively in the hearts of SHR 20 . The major cell types that showed TUNEL-positive nuclei were non-cardiomyocytes. The expression of bax remained unchanged during the transition to heart failure. However, there was increased expression of bcl-xL in the failing stage, whereas the expression of bcl-2 remained unchanged. Immunohistochemical studies revealed that Bcl-xL protein was up-regulated in the hearts of SHR 20 . In conclusion, non-cardiomyocyte apoptosis may play a contributory role in the remodelling that occurs in the transition from compensatory hypertrophy to decompensated heart failure. In addition, it is suggested that enhanced expression of bcl-xL plays an important role in the preservation of cardiomyocytes during this transition.

This study was designed to clarify whether gene expression in the cardiac sarcoplasmic reticulum [sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, ryanodine receptor and calsequestrin] changes in accordance with left ventricular functional alterations in the volume-overloaded heart. Further, the effect of the angiotensin II type 1 receptor antagonist, TCV-116, on the expression of these genes was also evaluated. Left ventricular fractional shortening was significantly increased at 7 days, had returned to control levels at 21 days, and had significantly decreased at 35 days after the shunt operation, compared with sham-operated rats. The level of SERCA mRNA was significantly decreased at both 21 days and 35 days after the shunt operation. The levels of ryanodine receptor and phospholamban mRNAs were significantly decreased at 35 days in shunt-operated rats. The decrease in the SERCA mRNA level preceded the development of cardiac dysfunction. The levels of SERCA and ryanodine receptor mRNAs were correlated positively with left ventricular fractional shortening (r = 0.73, P< 0.0001 and r = 0.61, P< 0.01 respectively). Attenuation of the decrease in left ventricular fractional shortening occurred on treatment with TCV-116. After the treatment with TCV-116, the levels of SERCA and phospholamban mRNAs were restored to the respective values in sham-operated rats. Ryanodine receptor mRNA levels remained unchanged after treatment with TCV-116. These results indicate that the down-regulation of SERCA and ryanodine receptor mRNA levels may be related to cardiac dysfunction in the volume-overloaded heart. In addition, treatment with an angiotensin II receptor antagonist may restore the altered sarcoplasmic reticulum mRNA levels to control levels, and this may result in attenuation of the functional impairment in the volume-overloaded heart.

Abstract —Platelet-derived growth factor-α receptor (PDGF-αR) expression is markedly elevated in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) when compared with normotensive rat strains, Sprague-Dawley, Wistar, and Wistar-Kyoto rats (WKY). This “almost-all-or-none” type of differential expression strongly suggests that PDGF-αR or its transcription-regulating mechanisms or factors are significantly related to genetic hypertension. To evaluate the role of PDGF-αR in vascular remodeling and hypertension, we have investigated the underlying molecular mechanism. We have recently shown that the regulatory domain responsible for this difference is localized to the PDGF-αR promoter region between –246 and –139, which contains an enhancer core sequence specific for CCAAT-enhancer binding proteins (C/EBPs). We defined the roles of this element for hypertensive strain-specific PDGF-αR gene transcription. DNA-protein binding studies by competition in electromobility shift and supershift assays revealed that 2 members, C/EBP-β and C/EBP-δ, are mainly responsible for DNA-protein complex formation; the former acts as a transcriptional repressor and the latter as an activator of the PDGF-αR gene, respectively. Western or Northern blot analyses supported evidence for high expression of C/EBP-δ seen only in SHR-derived VSMCs. Furthermore, forced expression of C/EBP-δ transactivated the transcriptional efficiency of the PDGF-αR gene even in WKY-derived VSMCs, whereas that of C/EBP-β had an opposite effect in SHR-derived VSMCs. These findings indicate that differential expression of members of the C/EBP family, mainly C/EBP-δ and possibly C/EBP-β, are responsible for the strain-specific gene transcription of PDGF-αR in VSMCs.