Biomedical subjects

S Katsuda

Publications and source records attributed to S Katsuda.

At least 37 records · Page 2Linked to original sources

PubMed2001

Expression of multidrug resistance protein and messenger RNA correlate with (99m)Tc-MIBI imaging in patients with lung cancer.

UNLABELLED: In vitro studies have shown that (99m)Tc-sestamibi (MIBI) is a transport substrate for the P-glycoprotein (Pgp) pump and the multidrug resistance-associated protein (MRP) pump. However, whether MRP and lung resistance protein (LRP) affect tumor accumulation and efflux of (99m)Tc-MIBI in lung cancer is not known. In this study, we explored whether Pgp and the other pumps, MRP and LRP, affect tumor accumulation and efflux of (99m)Tc-MIBI in lung cancer. METHODS: Thirty-four lung cancer patients who underwent surgery were examined. Before surgery, (99m)Tc-MIBI SPECT was performed 15 min and 180 min after injection, and early uptake, delayed uptake (L/Nd), and washout rate (L/Nwr) of (99m)Tc-MIBI were obtained. Pgp, MRP, and LRP expression were investigated by immunohistochemistry. The messenger RNA (mRNA) level of Pgp, MRP, and LRP was determined by real-time reverse-transcription polymerase chain reaction. The lung cancer (99m)Tc-MIBI images were correlated with protein and mRNA expression. RESULTS: The mean L/Nd of the Pgp (-) group was significantly higher than that of the Pgp (++) group (P = 0.0324). The Pgp (++) group had a higher L/Nwr than did the Pgp (-) group (P = 0.0269). The mean L/Nd of the Pgp mRNA low-expression group was significantly higher than that of the Pgp mRNA high-expression group (P = 0.0127). The Pgp mRNA high-expression group had a higher L/Nwr than did the Pgp mRNA low-expression group (P = 0.0825). No appreciable correlation was found between the lung cancer (99m)Tc-MIBI images and the expression of MRP or LRP on the level of protein or mRNA. CONCLUSION: These data suggest that an increased level of Pgp expression correlates with a low accumulation on delayed scans and a high L/Nwr of (99m)Tc-MIBI in lung cancer. Neither MRP nor LRP expression on the level of either protein or mRNA correlated significantly with tumor accumulation or efflux of (99m)Tc-MIBI in lung cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Comparison of [(18)F]FDG PET and (201)Tl SPECT in evaluation of pulmonary nodules.

UNLABELLED: Recent reports have indicated the value of [(18)F]FDG PET and (201)Tl SPECT in diagnosing lung cancer. In this study, we compared the diagnostic value of FDG PET and (201)Tl SPECT in the evaluation of pulmonary nodules. METHODS: Sixty-three patients with 66 pulmonary nodules suspected to be lung cancer on the basis of chest CT were examined by FDG PET and (201)Tl SPECT (early and delayed scans) within a week of each study. For semiquantitative analysis, the standardized uptake value (SUV) or the tumor-to-nontumor activity ratio (T/N) (or both) was calculated. All of these lesions were completely removed thoracoscopically or by thoracotomy and were examined histologically. RESULTS: Fifty-four nodules were histologically confirmed to be malignant tumors, and 12 were benign. Both techniques delineated focal lesions with an increase in tracer accumulation in 41 of 54 lung cancers. (201)Tl SPECT on early or delayed scans (or both) identified 4 additional lung cancers that FDG PET images did not reveal: 3 bronchioloalveolar carcinomas and a well-differentiated adenocarcinoma. FDG PET identified 3 additional lung cancers that (201)Tl SPECT images did not reveal; 2 of these lung cancers were <2 cm in diameter. The mean FDG SUV and T/N of bronchioloalveolar carcinomas (2.06 +/- 0.76 and 3.49 +/- 1.03, respectively) were significantly lower than those of poorly differentiated adenocarcinomas (5.55 +/- 2.01 [P = 0.026] and 8.23 +/- 2.16 [P = 0.01], respectively). However, no significant difference was found in (201)Tl T/N on early and delayed scans between bronchioloalveolar carcinomas (1.64 +/- 0.29 and 1.87 +/- 0.42, respectively) and poorly differentiated adenocarcinomas (1.58 +/- 0.32 and 2.76 +/- 1.36, respectively). Of the 12 benign nodules, FDG PET and (201)Tl SPECT showed false-positive results for the same 7 benign nodules (58.3%) (4 granulomas, 1 sarcoidosis, 1 inflammatory pseudotumor, and 1 aspergilloma). Negative FDG PET findings and positive (201)Tl SPECT findings were obtained only for bronchioloalveolar carcinomas or a well-differentiated adenocarcinoma but not for other histologic types of lung cancers or benign pulmonary nodules. CONCLUSION: No significant difference was found between FDG PET and (201)Tl SPECT in specificity for the differentiation of malignant and benign pulmonary nodules. The degree of differentiation of lung adenocarcinoma correlated with FDG uptake but not with (201)Tl uptake. Bronchioloalveolar carcinoma (a well-differentiated, slow-growing tumor) findings typically were positive with (201)Tl but were negative with FDG. The combination of FDG PET and (201)Tl SPECT may provide additional information regarding the tissue characterization of pulmonary nodules.

Adenocarcinoma↗

PubMed2000

Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study.

BACKGROUND: The precise molecular mechanism of Adriamycin-induced cardiomyopathy (ADR-CM) is still unknown. We address the demonstration of apoptotic myocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats. METHODS AND RESULTS: Until 8 weeks after the first administration of ADR, there was no increase in the number of labeled cells by terminal deoxynucleotidyl transferase assay (TUNEL method). Apoptotic indices increased significantly at weeks 9 and 10 in hearts of the ADR-treated group but not in those of the control group (0.42+/-0.12% versus 0.10+/-0.02% and 0.86+/-0.11% versus 0.09+/-0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-CM of rats. There was no significant difference in expression of p53 gene between the ADR group and the control group at either the message or the protein level. An overexpression of Fas antigen was shown in myocardial cells of ADR-treated hearts at weeks 9 and 10 by both Western blotting and immunofluorescent staining. Furthermore, we confirmed that neutralization of anti-Fas ligand antibody inhibited ADR-induced apoptosis. CONCLUSIONS: Apoptotic cell death was observed in the hearts of ADR-CM rats, and the number of apoptotic myocardial cells increased with the deterioration of morphological findings and cardiac function, indicating that apoptosis may be an important mechanism of loss of myocardial cells and cardiac dysfunction in ADR-CM. Apoptosis in ADR-CM rats is not p53-dependent but rather is executed through a Fas-mediated pathway.

Animals↗

PubMed2000

Subcutaneous treatment of p-tert-octylphenol exerts estrogenic activity on the female reproductive tract in normal cycling rats of two different strains.

Effects of p-tert-octylphenol (OP), an endocrine disrupting chemical (EDC), on the female reproductive tract of normal cycling Fischer 344 (F344) and Donryu rats were investigated. OP was subcutaneously injected at concentrations of 12.5, 25, 50 or 100 mg/kg for 28 days. The most notable changes were the disappearance of normal cyclicity in the 50 mg/kg or more OP-treated groups of both the strains, and the appearance of persistent estrus (PE) evident on examination of vaginal smears in the 100 mg/kg groups of both the strains, the effects being time- and dose-dependent. In PE rats of both the strains, the uterine morphology deviated from the normal for each estrous stage of the cycling rats, and proliferation in the endometrium was slightly increased. The data for uterine weights, luminal epithelial cell-heights and/or numbers of epithelial cells in the endometrium demonstrated equivocal alteration. In both the strains, the serum 17beta-estradiol (E2) levels were decreased with 50 mg/kg of OP or more. Serum concentrations of the administrated chemical were dose and duration-dependently increased in all the treated groups of both the strains. The results demonstrate that subcutaneous administration of OP at doses of 50 mg/kg or more exerts time- and dose-dependent estrogenic activity on the reproductive tract of normal cycling female Donryu and F344 rats, indicating similar qualitative sensitivity to the effects in both the strains. Vaginal cytology may be the most sensitive endpoint for the detection of estrogenic activity of potential EDCs using adult cycling rats.

Animals↗

PubMed2000

Irreversible effects of neonatal exposure to p-tert-octylphenol on the reproductive tract in female rats.

It has been known for many years that administration of androgens or estrogens at critical periods of development in mammals causes severe long-term effects on the endocrine/genital systems. The environmental pollutant p-tert-octylphenol (OP) possesses a weak but clear estrogen agonist activity in in vitro and in vivo studies. In the present study, effects of neonatal exposure to OP on the reproductive tract of female rats were investigated. Newborn female pups were injected with 100 mg/kg OP subcutaneously within 24 h after birth. Administration was repeated every other day until postnatal day 15 (total of eight doses). Before weaning, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) remained at low levels during OP exposure, although the serum FSH peak and the high LH level were obvious in the controls. Histologically, inhibition of uterine gland genesis was apparent. The day of vaginal opening was about 4 days earlier in OP-treated animals than in controls. Persistent estrus was consistently observed in OP-treated animals. Atrophic and polycystic ovaries without corpora lutea showed anovulation. In the endometrium, cell-proliferative activity and cell-death were increased and decreased, respectively, and expression of estrogen receptor alpha mRNA was apparent by in situ hybridization. Unexpectedly, endometrial hyperplasias appeared at 8 weeks of age. After ovariectomy, vaginal smears immediately became of castration type and the uterus was atrophied. These results suggested that neonatal exposure to a high dose of OP alters developmental hormonal secretion presumably due to a hypothalamo-pituitary-ovarian disorder, with accelerated vaginal opening, subsequent persistent estrus, and uterine endometrial hyperplasia. The changes in the uterus and vagina are ovary-dependent.

Animals↗

PubMed2000

Protective effect of bisoprolol on beta-1 adrenoceptor peptide-induced autoimmune myocardial damage in rabbits.

Idiopathic dilated cardiomyopathy is a severe disease of unknown etiology. Accumulating evidence suggests that agonist-like autoantibodies against the beta 1 adrenoceptor in the circulation of dilated cardiomyopathy may play an important role. The aim of this study was to evaluate the effects of the selective beta 1-adrenoceptor blocker, bisoprolol, on beta 1-adrenoceptor peptide induced autoimmune myocardial damage. In the animal model of autoimmune cardiomyopathy induced by active immunization of rabbits with beta 1-adrenoceptor peptide, bisoprolol was given at a dose of 3 mg/day throughout the study period. Our results showed high titer of anti-beta 1-adrenoceptor antibody in the immunized group throughout the study but not in the group receiving only bisoprolol. Cross-reactivity to beta 2 adrenoceptors was observed in some of the immunized rabbits, but disappeared almost entirely after 6 months. As compared to the beta 1-adrenoceptor peptide immunized group without bisoprolol treatment, bisoprolol treated beta 1-receptor peptide immunized group showed increase in the wall thickness and decreases in cavity dimension in anatomical measurements and only mild alterations in macro- and microscopic examinations. Thus, our study clearly demonstrated a beneficial effect of bisoprolol in rabbits who have developed autoimmune myocardial damage.

Adrenergic beta-Antagonists↗

PubMed2000

Modulation of collagen synthesis by tumor necrosis factor alpha in cultured vascular smooth muscle cells.

Collagen synthesis in vascular smooth muscle cells (SMCs) after exposure to tumor necrosis factor alpha (TNF-alpha) was investigated using a culture system. The synthesis of collagenase-digestible proteins (CDP) and noncollagenous proteins (NCP) was evaluated by the [3H]proline incorporation. It was shown that TNF-alpha markedly suppresses the incorporation of [3H]proline into both CDP and NCP in confluent cultures of SMCs but not in sparse cultures of the cells. Such a marked suppression by TNF-alpha was not observed in confluent bovine aortic endothelial cells and human fibroblastic IMR-90 cells. In confluent SMCs, the synthesis of CDP was more strongly inhibited by TNF-alpha than that of NCP. When the CDP synthesis was stimulated by transforming growth factor beta, TNF-alpha suppressed the stimulation in both confluent and sparse SMCs. Human SMCs synthesized types I, III, IV and V collagens; TNF-alpha markedly decreased the relative proportion of types IV and V. It was therefore suggested that TNF-alpha modulates the collagen synthesis by SMCs depending on their cell density and modifies the formation of atherosclerotic lesions.

Animals↗

PubMed2000

FDG PET in the evaluation of the aggressiveness of pulmonary adenocarcinoma: correlation with histopathological features.

2-[Fluorine-18]fluoro-2-deoxy-d-glucose (FDG) uptake within the primary lesion correlates with survival on positron emission tomography (PET) studies of patients with non-small cell lung cancer. The more metabolically active the tumour, the worse the outcome. The aim of this study was to determine whether a correlation exists between aggressiveness as determined by pathology and the findings of FDG PET in pulmonary adenocarcinoma. Thirty-five patients with 38 adenocarcinomas of the lung were studied. All patients underwent thoracotomy within 4 weeks of the FDG PET study. For semiquantitative analysis, standardized uptake values (SUVs) were calculated. Patients were classified into high SUV (> or = 4.0) and low SUV (<4.0) groups. The degree of FDG uptake (SUVs) in primary lung lesions was correlated with the histopathological features of aggressiveness (pleural involvement, vascular invasion or lymphatic permeation). The mean SUV of aggressive adenocarcinomas (4.36+/-1.94, n = 22) was higher than that of non-aggressive ones (1.53+/-0.88, n = 16) (P < 0.0001). Tumours with a high FDG uptake have a significantly higher likelihood of aggressiveness than those with a low FDG uptake (P = 0.0004). Analysis by the Kaplan-Meier methods revealed that the groups had different prognoses (log-rank test, P = 0.0099). The high SUV group had a significantly worse prognosis. In conclusion, a correlation was seen between aggressiveness as determined by pathology and glucose metabolism as measured by FDG PET in adenocarcinoma of the lung. FDG PET may be used as a non-invasive diagnostic technique in measuring aggressiveness and prognosis in patients with pulmonary adenocarcinoma.

Adenocarcinoma↗

PubMed2000

Time-dependent change in baroreflex control capacity of arterial pressure by pentobarbital anesthesia in rabbits.

The present study is designed to investigate the time-dependent effect of pentobarbital anesthesia on the baroreflex arterial pressure (AP) control system in rabbits. The overall AP control capacity of the baroreflex system was assessed with mean arterial pressure (MAP) responses to the rapid mild hemorrhage (2 ml/kg body weight) and an overall open-loop gain (G) of the system. The G value was determined by means of the following formula: G = delta API/delta APS-1, where delta APl is an immediate MAP fall and delta APS a steady-state fall after the rapid hemorrhage. Prior to the experiment, two catheters for AP measurement and hemorrhage were chronically in-dwelt in the aortic arch via the left subclavian and left common carotid arteries, respectively. Control mean arterial pressure averaged for 30 sec before the rapid hemorrhage (CMAP), delta API and delta APS significantly increased and reached the maximal value at 14 min (CAMP: p < 0.01) and 28 min (delta API: p < 0.01 and delta APS: p < 0.01) after the intravenous injection of sodium pentobarbital in a 25.0 mg/kg dose, respectively. These values gradually decreased in the course of time and tended to recover to near the preanesthetic level at 77-98 min after the anesthesia. The G value significantly decreased from 7.3 in the conscious state to 1.5 at 28 min after the anesthesia (p < 0.001), gradually increased with lapse of time and recovered to near the preanesthetic level at 77-98 min after the anesthesia. No significant difference in G was observed between in the conscious and anesthetized states beyond 70 min after the anesthesia (p > 0.05). These findings suggest that pentobarbital sodium exerts a time-dependent inhibitory effect on the baroreflex system but does not significantly affect the overall AP control capacity of the baroreflex system itself at least 70 min after the intravenous administration at a dose of 25.0 mg/kg.

Adaptation, Physiological↗

PubMed2000

Papain-hydrolyzed pork meat reduces serum cholesterol level and premature atherosclerosis in dietary-induced hypercholesterolemic rabbits.

The effects of the low-molecular-weight fraction of papain-hydrolyzed pork meat (LMF) on the plasma cholesterol level and the generation of atherosclerosis were studied in rabbits fed a cholesterol-enriched diet. In LMF-fed rabbits, the plasma and liver cholesterol concentrations were both significantly lower (p<0.0 1) than in rabbits fed untreated pork meat (PM). Similarly, the cholesterol concentrations of the chylomicron and VLDL fractions were significantly lower in LMF-fed rabbits than in rabbits fed PM. Deposition of lipid in transverse sections of the aortic arch was significantly less in rabbits fed LMF than in those fed PM. Electron microscopic studies revealed preventive effects against premature atherosclerotic lesions in the aorta of rabbits fed LME These results indicate that LMF has a hypocholesterolemic action and preventive effects against premature atherosclerosis.

Animals↗

PubMed2000

Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits.

OBJECTIVE: We investigated apoptosis, i.e., programmed cell death, in steroid induced osteonecrosis in a rabbit model. METHODS: Forty-four adult Japanese White rabbits were divided into 3 groups: Group A were untreated controls and had a subsequent 8 week no-treatment period; Group B received intramuscular injection of methylprednisolone 4 mg/kg once weekly for 4 weeks; and Group C received the same treatment and had a subsequent 8 week no-treatment period. At the end of each period, all animals were sacrificed and tissue samples were obtained from the femur and humerus for histopathologic examination. Terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) biotin nick end labeling (TUNEL) was used to detect fragmented DNA known to be associated with apoptotic cell death. RESULTS: Group A rabbits did not develop osteonecrosis-like lesions (ONL) in the femur and humerus, and few TUNEL positive cells were observed in bone marrow cells. In Group B, ONL developed in 11/15 rabbits, and many TUNEL positive cells were found in the area surrounding ONL. In Group C, ONL were found in 6/10 rabbits, but only a few TUNEL positive cells were present around the lesion. CONCLUSION: These findings revealed that apoptosis occurs in the early stage of steroid induced osteonecrosis.

Animals↗

PubMed2000

Comparison of pulse-wave velocity in different aortic regions in relation to the extent and severity of atherosclerosis between young and older Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits.

The present study was performed to investigate the effects of the development of atherosclerosis on foot-to-foot pulse-wave velocity (PWV) from the ascending aorta to different positions along the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12 and 22-24 months old, in relation to the percentage fractional lesioned area (PFLA) in different aortic regions through which the pulse wave travels, as well as the rheological and pathohistological properties of the aortic wall. PWV, when measured in the KHC rabbit from the ascending aorta to each aortic position, showed the highest value on passage through the aortic arch, decreased with conduction to the distal thoracic aorta, reached the minimal value on passage to the distal thoracic aorta or to the middle abdominal aorta in the 10-12- and 22-24-month-old animals respectively, and increased gradually on conduction to the iliac artery. PWV at all aortic regions examined was significantly greater in the 22-24-month-old than in the 10-12-month-old KHC rabbits. PFLA, when measured in the aortic region from the ascending aorta to each aortic position, was maximal in the aortic arch and decreased gradually towards the peripheral aorta in both age groups. PFLA in the 22-24-month-old group was significantly greater than that in the 10-12-month-old group in all aortic regions examined. The atherosclerotic aortic wall showed a significantly lower elastic modulus in the young KHC rabbits compared with age-matched normal rabbits. A significantly higher elastic modulus was observed in the older KHC rabbits compared with that in the younger animals of both strains, associated with the progression of sclerosis. These findings indicate that the increase in PWV is due mainly to an increase with aging in the extent and severity of atherosclerosis in vessels in which the pulse wave travels.

Aging↗

PubMed2000

Correlation of Glut-1 glucose transporter expression with.

Positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [18F]FDG PET was performed 40 min after i.v. injection of 185 MBq [18F]FDG. For semi-quantitative analysis of [18F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P < 0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n = 7) (2.86% +/- 7.56% and 1.25 +/- 0.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n = 23) (54.83% +/- 25.64%, P < 0.0001, and 3.94 +/- 1.93, P = 0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n = 11, SUV 1.47 +/- 0.63; intensities 2 and 3, n=23, SUV 4.78 +/- 2.13; P < 0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n = 34, r = 0.658, P < 0.01). Overexpression of Glut-1 correlated with high [18F]FDG uptake. These findings suggest that Glut-1 expression is related to [18F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [18F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [18F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1999

Active immunization of combined beta1-adrenoceptor and M2-muscarinic receptor peptides induces cardiac hypertrophy in rabbits.

BACKGROUND: The high prevalence of patients with dilated cardiomyopathy (DCM) with anti-beta1-adrenoceptor and/or anti-M2-muscarinic receptor autoantibodies in their sera has been observed. However, the pathophysiological role of these autoantibodies in the development of cardiomyopathy is unknown. We previously reported an experimental model of early-stage DCM-like cardiomyopathy induced by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta1-adrenoceptor or M2-muscarinic receptor. Because approximately half the sera of patients with DCM that recognize one of the two receptor sequences also recognize the second sequence, a model was created in rabbits simultaneously immunized with the synthetic peptides corresponding to the second extracellular loop of the beta1-adrenoceptor and M2-muscarinic receptor. METHODS AND RESULTS: All rabbits (n = 8) immunized with both peptides had a high titer of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in their sera, whereas none of the sera from control rabbits injected with saline (n = 9) was positive. No significant cross-reaction with peptides other than those used for immunization was found. The weight of the hearts of immunized rabbits increased significantly. The hearts of immunized rabbits showed marked concentric left ventricular hypertrophy with mild inflammatory cell infiltration. In these rabbits, mild or moderate interstitial fibrosis was also observed. In electron micrographs, immunized rabbits showed focal myofibrillar lysis, loss of myofilament, and a marked increase in the number of mitochondria and deposition of dense granules in both sarcoplasm and myofibrils. Conversely, one of the control rabbits showed scant mononuclear cell infiltration. However, in this control rabbit, no significant alteration was found by electron microscopy. CONCLUSION: Our results showed the coexistence of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in the sera has pathophysiological importance, shown by their ability to induce cardiac hypertrophy in rabbits.

Amino Acid Sequence↗

PubMed1999

Coronary ectasia in familial hypercholesterolemia: histopathologic study regarding matrix metalloproteinases.

A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over the entire coronary artery tree had been treated with several kinds of lipid-lowering single or combined drug therapies using clofibrate, compactin, cholestyramine, probucol, and pravastatin, and LDL-apheresis. During the 19-year follow-up, he suffered myocardial infarction three times and some of the ectatic coronary segments became enlarged, others narrowed, and one of them occluded in spite of the treatment. At the age of 58, he died after a fourth cardiac attack and subsequent cardiogenic shock. The autopsy indicated that his three coronary arteries showed diffuse ectatic changes and the largest lumen diameter of the left anterior descending artery was 25 mm, of the circumflex artery 12 mm, and of the right coronary artery 13 mm. The ectatic artery wall was not thick and the major part of the lumen was occupied by organized thrombi. Microscopic examinations showed that the larger the diameter of the lumen, the more severe the structural damage of the intima and tunica media and the larger the number of infiltrated cells, including lymphocytes, macrophages, and plasma cells. Immunoreactivity against matrix metalloproteinase (MMP)-1, and MMP-2 was observed in smooth muscle cells, macrophages, lymphocytes, and endothelial cells of the vasa vasorum or neovasculature. MMP-9 immunoreactivity was also localized in intimal foamy macrophages and round cells (macrophages and lymphocytes) of the media and adventitia. MMP-1 increased with the lumen diameter of the ectatic arteries. The ratio of immunoreactivity against both MMP-2 and MMP-9 to that against tissue inhibitor of metalloproteinase (TIMP)-2 also increased with the lumen diameter, but it no longer increased when the diameter was over 10 mm. These observations suggest that the MMP-TIMP system appears to play a significant role in the development of coronary ectasia

Adult↗

PubMed1998

Inhibitory effects of uterine endometrial carcinogenesis in Donryu rats by tamoxifen.

The effects of tamoxifen (TAM) on uterine carcinogenesis were investigated in female Donryu rats. The effects were initiated by a single intrauterine treatment with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at a dose of 20 mg/kg body weight via the vagina at 10 weeks of age. TAM tubes (cholesterol tubes containing 50% TAM) were implanted into the backs of the rats for 13 months (full TAM group) or for the second-half of this period (half TAM group). In the control group treated with ENNG alone, various proliferative lesions were induced in the uterine endometrium and the incidence of endometrial adenocarcinomas was about 30%. In contrast, the uteri in both TAM-treated groups showed severe atrophy and the incidences of uterine proliferative lesions were limited to a few endometrial hyperplasias in the half TAM group. Most of the vaginas in both TAM-treated groups showed mucification, while cornification was common in the vaginal epithelium of controls. The ovaries demonstrated similar atrophy with cystic follicles and no corpora lutea in all groups. Other estrogen responsive endocrine organs, such as the pituitaries and adrenals, were small in the TAM-treated groups. Serum estrogen levels in the TAM-treated groups were lower than in the control group but progesterone levels did not differ. These results indicated that TAM acts as an anti-estrogen on the adult rat uterus, inhibiting the development of endometrial adenocarcinomas initiated by ENNG.

Adrenal Glands↗

PubMed1997

Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits.

An experimental model of early-stage cardiomyopathy was created by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta-adrenoceptors or M2-muscarinic receptors. Thirty male rabbits were used and divided into three groups: a control group (n = 10), a group immunized with the peptide corresponding to the beta-adrenoceptor (beta 1 group) (n = 10) and a group immunized with the peptide corresponding to the M2-muscarinic receptor (M2 group) (n = 10). If the sera from both groups of immunized rabbits high-titres of anti-peptide antibodies were found throughout the study period but not in the sera from control rabbits or in the preimmune sera of immunized rabbits. No significant cross-reaction with peptides other than those used for immunization was found. The myocardial receptor density of both immunized groups displayed a strong trend toward receptor up-regulation. This was significant in the beta 1 group but not in the M2 group. Both groups of immunized rabbits displayed significantly enlarged ventricles and thinner walls, as compared with the control group. However, in contrast to the beta 1 group, which showed enlarged cavities in both left and right ventricles, the M2 group was mainly affected in the right ventricles. Moreover, morphological examinations of the hearts of rabbits from both immunized groups demonstrated focal myofibrillar lysis, loss of myofilament, mitochondrial swelling and condensation, sarcoplasmic vacuolation, deposition of dense granules in the sarcoplasm and the myofibrils. One of the sex control rabbit hearts which were examined showed mild degenerative changes in the myocardium and scant mononuclear cell infiltration. However, when all the control rabbit hearts were examined by electron microscopy, no significant alterations were found. These results suggest that immunization by peptides, corresponding to the target sequences for anti-receptor autoantibodies in idiopathic dilated cardiomyopathy, induces morphological changes in the heart similar to those found in the human disease.

Amino Acid Sequence↗

PubMed1997

In vitro and in vivo anti-platelet effects of enzymatic hydrolysates of collagen and collagen-related peptides.

Collagen-related peptides, Gly-Pro-Arg and its analogues, were examined for their inhibitory effects on platelet aggregation induced by the addition of ADP. Human platelet aggregation was suppressed by more than 50% with each of Gly-Pro-Arg and such Gly-Pro-Arg-containing peptides as Gly-Pro-Arg-Gly, Gly-Pro-Arg-Gly-Pro, Gly-Pro-Arg-Pro-Pro, and Gly-Pro-Arg-Pro-Pro-Pro at a concentration of 0.3 mM. The inhibitory effects of these peptides were about 10 times higher in human PRP than in rat PRP. Other Gly-Pro-Arg analogues such as Sar-Pro-Arg, Gly-Pro-Lys, Gly-Ala-Arg, and Ala-Gly-Pro-Arg had no inhibitory effect at a concentration from 0.1 to 0.8 mM even in human PRP. Intravenous and oral administrations of Gly-Pro-Arg and enzymatic hydrolysates of collagen suppressed the decrease in platelet count for endotoxin-induced DIC in rats. Collagen itself has been regarded as a potent inducer of platelet aggregation, but these findings suggest that collagen-related peptides and enzymatic hydrolysates of collagen prevent platelet aggregation.

Animals↗