Biomedical subjects

Kazuhiko Uchida

Publications and source records attributed to Kazuhiko Uchida.

At least 19 recordsLinked to original sources

PubMed2006

Gene expression profiling defined pathways correlated with fibroblast cell proliferation induced by Opisthorchis viverrini excretory/secretory product.

AIM: To investigate the mechanism of fibroblast cell proliferation stimulated by the Opisthorchis viverrini excretory/secretory (ES) product. METHODS: NIH-3T3, mouse fibroblast cells were treated with O. viverrini ES product by non-contact co-cultured with the adult parasites. Total RNA from NIH-3T3 treated and untreated with O. viverrini was extracted, reverse transcribed and hybridized with the mouse 15K complementary DNA (cDNA) array. The result was analyzed by ArrayVision version 5 and GeneSpring version 5 softwares. After normalization, the ratios of gene expression of parasite treated to untreated NIH-3T3 cells of 2-and more-fold upregulated was defined as the differentially expressed genes. The expression levels of the signal transduction genes were validated by semi-quantitative SYBR-based real-time RT-PCR. RESULTS: Among a total of 15,000 genes/ESTs, 239 genes with established cell proliferation-related function were 2 fold-and more-up-regulated by O. viverrini ES product compared to those in cells without exposure to the parasitic product. These genes were classified into groups including energy and metabolism, signal transduction, protein synthesis and translation, matrix and structural protein, transcription control, cell cycle and DNA replication. Moreover, the expressions of serine-threonine kinase receptor, receptor tyrosine kinase and collagen production-related genes were up-regulated by O. viverrini ES product. The expression level of signal transduction genes; pkC, pdgfr alpha, jak 1, eps 8, tgf beta 1i4, strap and h ras measured by real-time RT-PCR confirmed their expression levels to those obtained from cDNA array. However, only the up-regulated expression of pkC, eps 8 and tgfbeta 1i4 which are the downstream signaling molecules of either epidermal growth factor (EGF) or transforming growth factor-beta (TGF-beta) showed statistical significance (P < 0.05). CONCLUSION: O. viverrini ES product stimulates the significant changes of gene expression in several functional categories and these mainly include transcripts related to cell proliferation. The TGF-beta and EGF signal transduction pathways are indicated as the possible pathways of O. viverrini-driven cell proliferation.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Mental effect of cholesterol in males: protective effect?

BACKGROUND: While the benefits of low cholesterol for physical health are not in doubt, a potential negative aspect of low cholesterol for mental health is suggested by several studies. To examine the association between cholesterol and mental health, the authors performed an observational study. METHOD: From April 1995 to March 2002, a series of questionnaires pertaining to physical activity, food consumption, alcohol, coffee, smoking, and mental health (12 item-version of General Health Questionnaire: GHQ-12) were administered to 1972 employees in Japan. Subjects with less than 150 mg/dL of total cholesterol (very low cholesterol cohort) and other subjects (control cohort) were followed up for one to six years, and their mental health compared using GHQ caseness (GHQ-12 scores more than 3). RESULTS: Kaplan-Meier survival curves revealed that the very low cholesterol cohort had significantly greater GHQ caseness than the control cohort. Notably, this finding applied to males but not to females. After adjustment for general health, Cox's proportional hazards regression model confirmed this association in males only. The survival curves of control cohort were significantly different between males and females whereas those of very low cholesterol cohort were not. LIMITATIONS: GHQ caseness was regarded as "death" in the survival analysis. As such, it is not possible to differentiate between transient and persistent mental dysfunction and therefore may lead to overestimation of GHQ caseness over observational years. CONCLUSION: The present findings suggest that very low cholesterol may be associated with worse mental health in males and conversely and interestingly indicate that moderate (but not very low) cholesterol levels may protect mental health in males.

Adult↗

PubMed2006

Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines.

BACKGROUND: Several studies have demonstrated that intratumoral expression of catabolizing and anabolizing enzymes for 5-fluorouracil (5-FU) is important in the response of cancers to 5-FU-based chemotherapy. We investigated the influence of other chemotherapeutic agents or cytokines, which are often administered for enhancing the efficacy of 5-FU, on the tumoral expression of 5-FU-associated enzymes, i.e., dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), orotate phosphoribosyl transferase (OPRT), and thymidine phosphorylase (TP). METHODS: Human colon cancer cell lines (HT-29, Caco-2, and DLD-1) were incubated with 5-FU and with 5-FU combined with cisplatin, camptothecin, paclitaxel, mitomycin C, interferon, or TNF-related apoptosis-inducing ligand. mRNA expression of 5-FU-associated enzymes was assessed by real-time PCR. Activity of each enzyme and intracellular 5-FU accumulation after incubation with such agents were also evaluated. RESULTS: Each agent had a synergistic effect on the cytotoxicity of 5-FU. All chemotherapeutic agents other than cytokines induced marked alteration of the mRNA expression profile of 5-FU-associated enzymes; depression of DPD, elevation of TS, and slight suppression of OPRT and TP. In accordance with mRNA expression, enzyme activity of DPD was significantly depressed by such agents. Furthermore, although 5-FU itself increased DPD mRNA expression, a mechanism considered to be related to the acquisition of 5-FU resistance, the addition of cisplatin or camptothecin significantly inhibited the 5-FU-induced elevation of DPD. CONCLUSIONS: 5-FU-associated enzymes in colon cancer cells were greatly influenced by various chemotherapeutic agents; in particular, DPD expression was depressed. These results appear important in planning chemotherapy and also in understanding the development of adverse effects of 5-FU.

Antimetabolites, Antineoplastic↗

PubMed2006

Quantitation of thyroid peroxidase mRNA in peripheral blood for early detection of thyroid papillary carcinoma.

We applied quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to detect tissue-specific mRNAs in circulating cancer cells for the diagnosis of early-stage cancer. By Northern blotting, the thyroid peroxidase gene (TPO) was strictly expressed in the thyroid. We also used RT-PCR to examine TPO and thyroid stimulating hormone receptor (TSHR) mRNAs in peripheral blood in 33 thyroid papillary carcinoma patients at stages I (23 cases), II (8 cases) and III (3 cases), 49 noncancer patients with benign thyroid diseases, and 20 healthy volunteers. TPO mRNA was detected in 14 of 23 (61%) cases of stage I carcinoma but only 2 of 49 cases with benign thyroid disease. TPO mRNA was not detected in 20 healthy volunteers. By real-time quantitative RT-PCR, the estimated number of thyrocytes in the circulation ranged from 0.24 and 2700 cells per milliliter of whole blood in 7 of 9 patients at stages I and II, and thyrocyte number did not correlate with tumor size or serum thyroglobulin level. Our results might suggest that detection and quantification of tissue-specific mRNAs (e.g., TPO) in peripheral blood could serve as a means to identify potential tumor markers at early stages of cancer.

Adult↗

PubMed2006

The challenges of occupational health service centers in Japan.

The improvement of occupational health conditions in Small- and medium-scale enterprises (SMEs) is the most crucial issue in occupational health in Japan today. Improvement will depend on how occupational health services are provided to SMEs. Recently, Occupational Health Service Centers (OHSCs) providing occupational health services for SMEs have become more firmly established and expectations for further improvement in quality and quantity are high. In this way it is hoped that the challenges of providing "occupational health for all" can be met.

Industry↗

PubMed2005

Genetic and environmental determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a densely infested area in Nakhon Phanom, northeast Thailand.

Infection with Opisthorchis viverrini (OV) is associated with cholangiocarcinoma. OV is common in northeast Thailand, but less than 10% of the inhabitants develop cholangiocarcinoma. Animal experiments suggest that OV infection alone does not cause cholangiocarcinoma, and thus other environmental and genetic factors may play a role in causation. We conducted a population-based case-control study in which sex, age and place of residence were matched individually. Polymorphisms of GSTM1 and GSTT1 alone were not associated with risk for cholangiocarcinoma, while an elevated level of antibodies against OV (ELISA) > or = 0.200 was the strongest risk indicator (odds ratio as compared to that <0.200 = 27.09 [95% confidence interval (CI): 6.30-116.57]. Compared to subjects who had a normal antibody range and the wild-type GSTM1 gene, those who had elevated antibodies had higher odds ratios of 10.34 (95% CI: 1.31-81.63) [corrected] for wild-type GSTM1 and 18.00 (95% CI: 3.33-97.40) [corrected] for the null variant thereof, respectively. Past and current regular drinkers of alcohol had higher risk [odds ratio = 5.39 (95% CI: 1.11-26.06) and 4.82 (95% CI: 1.29-18.06), respectively]. Eating fermented products was an independent risk factor. Smokers or consumers of fermented fish had substantially increased risk if they were past or current drinkers. Infection with OV correlates strongly with cholangiocarcinoma, susceptibility to which may be possibly associated with GSTM1 polymorphism. Alcohol may affect metabolic pathways of endogenous and exogenous nitrosamines.

Animals↗

PubMed2005

Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines.

The potential anti-proliferation effect of interferon-alpha (IFN-alpha) against hepatocellular carcinoma (HCC) and its growth inhibitory mechanisms remain unclear. We examined four human HCC cell lines and every cell line had the anti-proliferative effect of IFN-alpha. The PLC/PRF/5 cell line, which expressed the IFN receptor most abundantly, responded most effectively to IFN-alpha stimulation. Here, we delineate the anti-proliferative effect of IFN-alpha via the MAPK pathway in human HCC cell lines. IFN-alpha retarded G1/S transition with no evidence of apoptosis and inhibited cell proliferation. IFN-alpha diminished the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of signal transducers of activation and transcription1 (STAT1) or Janus kinase1 (JAK1) suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-alpha. These results suggest that IFN-alpha induces anti-proliferative signaling via the JAK/STAT pathway downstream of IFN-alpha receptors and may reduce the growth stimulation signaling by cross-talk with the MEK/ERK pathway without IFN-alpha-induced transcription.

Carcinoma, Hepatocellular↗

PubMed2005

Alterations of DNA copy number and expression in genes involved in cell cycle regulation and apoptosis signal pathways in gamma-radiation-sensitive SX9 cells and -resistant SR-1 cells.

In the present study, genomic differences related to sensitivity to radiation were examined by comparative genomic hybridization and GeneChip 45K microarray in SX9 cells (radiation-sensitive) and their parental line, SR-1 (radiation-resistant). SX9 cells have defective DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity. DNA-PKcs is a DNA double-strand break repair protein that maintains chromosomal stability through nonhomologous end joining. However, the molecular basis of the radiation sensitivity of SX9 cells is unclear. Flow cytometry analysis showed that SR-1 and SX9 cells had a larger G2/M-phase population at 12 h after 4 Gy gamma irradiation, while only SR-1 cells progressed to G1/S at 24-36 h. SX9 and SR-1 cells had similar patterns of DNA copy number alteration, but the gains were observed on chromosome 9 (cent-E2), 11 (cent-A3), and 12 (C1-E) only in SX9 cells. Expression of genes located on those regions is higher in SX-9 cells than in SR1 cells, and the regions include genes associated with apoptosis and cell cycle regulation. Time-course data for gene expression at 0, 1, 3, 6 and 12 h after 4 Gy gamma irradiation revealed that the genes whose expression was altered in SX9 cells but not in SR-1 cells are in 16 clusters. Three of these clusters included genes for cell cycle regulation: JNK, PKC (PRKC) and ceramide cascade protein. These results suggest that amplification and altered expression of genes associated with cell cycle and apoptosis regulators in DNA-PK-deficient SX9 cells affect the differences in response to gamma radiation between SX9 and SR-1 cells.

Animals↗

PubMed2005

Microsatellite instability and expression of mismatch repair genes in sporadic endometrial cancer coexisting with colorectal or breast cancer.

The molecular background of sporadic endometrial cancer coexisting with colorectal or breast cancer is not clear. We investigated microsatellite instability (MSI) and status of mismatch repair (MMR) gene product, MLH1, MSH2 and MSH6, in 63 sporadic endometrial cancers coexisting with colorectal or breast cancer. Sixteen sporadic endometrial cancers with colorectal cancers (EC), 26 sporadic endometrial cancers with breast cancer (EB) and 21 endometrial cancers without a coexisting cancer (control) were analyzed. EC had the highest frequency of MSI among the 3 groups (EC, 69%; EB, 23%; and control, 43%). Incidence of low-frequency MSI was significantly higher in EC (38%). Among endometrial cancer cases diagnosed before age 50, all high-frequency MSI (MSI-H) cases belonged to EC. Interestingly, incidence of MSI-H was significantly higher in tamoxifen-non-treated cases (75%) than that of treated cases (14%). These results suggest that alterations in MMR genes appear to be involved in carcinogenesis of EC but seem to be uncommon in those of EB. Presence of MSI in sporadic endometrial cancer may be a useful marker to predict the risk of colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Gene expression profiles correlate with the morphology and metastasis characteristics of renal cell carcinoma cells.

Renal cell carcinoma (RCC) shows various clinical behaviors, and currently surgical modalities are the only effective therapy against this cancer. To discern the genomic background affecting clinical characteristics such as metastasis, we analyzed the gene expression profiles of the RCCs by DNA microarray using cell lines originating from primary or metastatic lesions. RNA was extracted from ten SKRC RCC cell lines and gene expression profiling was performed using a cDNA microarray of nearly 4,000 human cDNA clones. We compared the gene expression profiles between these SKRC cell lines and the normal renal proximal tubular cell line and among SKRC cell lines that showed different characteristics. The clustering of the selected 62 genes revealed similar profiling patterns between SKRC-17 and SKRC-29 cells that were derived from metastatic RCC lesions. Another cell line from a metastatic lesion, SKRC-52, with a unique spindle-shaped morphology, had a different pattern of expression profiling from the other cell lines. We found several genes up-regulated in the cell lines from metastatic lesions; transgelin, which is reportedly involved in cell proliferation and migration, was up-regulated in SKRC-52. The unique profiling pattern of gene expression clearly correlated with cell morphology and metastatic potential. Such profiling might contribute to identifying the genes involved in the clinical characteristics of RCC.

Carcinoma, Renal Cell↗

PubMed2004

[Fatigue estimation of visual display terminal (VDT) workers by physiological data--preliminary study of a new computer program for VDT work analysis].

The methods for assessing VDT workload based on individual capabilities are necessary to evaluate general fatigue by VDT work. We have developed a new computer program for assessing data entry performance of each individual. Four healthy male volunteers conducted a data entry task at their own pace using this program under a controlled environment. They performed the task for 30 minutes twice with 10 minutes rest between them. As a result, the average number of inputs was 133.2 characters/min in the first task and 129.1 characters/min after taking the rest. The error rate was 8.6% and 10.6% in each task. This program was useful to evaluate their data entry performance. We also reported our concern with a drop in nasal skin temperature that was observed during these VDT tasks.

Adult↗

PubMed2004

[Effect of the Training Program at Occupational Health Training Center (OHTC) on the attitude of occupational health residents].

University of Occupational and Environmental Health (UOEH) conducts three courses in postgraduate education of occupational health (OH). Graduates of UOEH who have already received a basic education in OH can participate in any course and are trained to play an appropriate role as an occupational physician (OP). We operate the training program to provide practical knowledge and skills as well as to encourage interest in occupational health and to promote a further understanding of the role of the OP. In this study we evaluated changes in attitude of participants and the effectiveness of our program by an anonymous questionnaire. The subjects were all 19 participants of the 3-month program conducted between September 2003 and February 2004 as a part of the postgraduate education following several years of clinical experience. They were expected to be occupational physicians with a clinical specialty. The data were collected from questionnaires handed out at the beginning and the end of the program. The questionnaire included 8 items on the attitude toward occupational health. The subjects answered the questions according to a scale of 1 to 7. Data analysis was performed using the unpaired t-test by SPSS. The results suggested that our training program had a positive effect on trainees. Interest in occupational practice (P < 0.05) and willingness to act as a full-time occupational physician in a large company (P < 0.05) increased significantly. When considering the positive correlation between willingness to act as an OP and interest in a field that has some overlap between the speciality and occupational health, it was thought that developing a vision as an OP with respect to their career was important for training. However, in some clinical fields it may be difficult to define a relationship between the clinical speciality and occupational health. Understanding the role of an OP (P < 0.05) and self-confidence in playing an appropriate role as an OP (P < 0.05) also showed significant improvement. On the other hand, fourteen of the trainees (74%) did not have enough confidence to play a role as an OP even after completion of the program. In this study, the questionnaire we used was anonymous and did not include items concerning various attributes of the subjects. Therefore it was not possible to analyze changes of attitude at the individual level. We recognize the need to improve the program and are preparing a new version of the educational program with emphasis on understanding company organization activities and practical skills for problem solving. Opportunities to consider association between clinical speciality and occupational health are also included in this new version. We hope that the new program will further encourage trainees.

Clinical Competence↗

PubMed2004

Gene expression profiling identifies platelet-derived growth factor as a diagnostic molecular marker for papillary thyroid carcinoma.

PURPOSE: Cancer diagnostics and therapeutics are often based on clinically relevant markers that are expressed specifically in a malignant tissue at levels higher than in normal tissue. We examined potential markers for papillary thyroid carcinoma (PTC) by monitoring PTC-specific gene expression using cDNA microarray. EXPERIMENTAL DESIGN: Gene expression profiles for PTC tissue, normal thyroid tissue, and healthy peripheral blood cells were compared by use of a human 4000-gene cDNA microarray. Protein expressions of the up-regulated genes in PTC were examined in thyroid tissues by immunohistochemistry. RESULTS: Sixty-four genes were overexpressed in PTC tissue relative to normal thyroid tissue and healthy peripheral blood cells. The genes that were up-regulated in PTC were involved in cell cycle regulation, DNA damage response, angiogenesis, and oncogenesis. Among these genes, basic fibroblast growth factor and platelet-derived growth factor were identified by immunochemical methods as proteins that are specifically expressed at high levels in thyroid neoplasms. Basic fibroblast growth factor, which has been identified as a biomarker for PTC, was overexpressed in 54% of PTC cases, 67% of follicular thyroid carcinomas, and 36% of benign thyroid neoplasms. Platelet-derived growth factor was overexpressed in 81% of PTC cases and 100% of follicular carcinomas, but was immunonegative in normal thyroid tissues and benign thyroid neoplasms. CONCLUSIONS: Platelet-derived growth factor may be a potential biomarker for PTC and follicular carcinoma. Expression profile analysis using a microarray followed by immunohistochemical study can be used to facilitate the development of molecular biomarkers for cancer.

Carcinoma, Papillary↗

PubMed2004

Amplicon profiling reveals cytoplasmic overexpression of MUC1 protein as an indicator of resistance to platinum-based chemotherapy in patients with ovarian cancer.

Chromosomal gains of 1q21-q22 and 13q12-q14 were closely related with the chemoresistance of patients with ovarian cancer in our previous CGH (comparative genomic hybridization) study. We conducted the present study to determine the amplified genes on chromosome 1q. Comparisons of relative copy numbers of clinically platinum-sensitive ovarian tumors (CR-group, n=14) and platinum-resistant tumors (PD-group, n=14) were carried out using real-time PCR from ten different gene loci on chromosome 1q. Increased copy numbers were frequently observed in PD-group tumors, especially in the region between WI-8123 and MUC1. Relative copy number of MUC1 over 1.5 was observed in 13 (92%) of 14 PD-group tumors and 3 (21%) of 14 CR-group tumors (p<0.05). Moreover, cytoplasmic expressions of MUC1 protein were significantly higher in PD-group than those in CR-group (p<0.01). We concluded that the cytoplasmic overexpression of MUC1 might be an indicator of resistance to platinum-based chemotherapy and a prognostic marker in ovarian cancer.

Aged↗

PubMed2003

Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand.

The liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) is a major liver cancer in Northeast Thailand. The molecular basis of this ICC is poorly understood. To address possible roles of the DNA mismatch repair (MMR) system in ICC carcinogenesis, a fluorescence-labeling PCR/laser scanning technique with high sensitivity was employed to analyze genomic instability in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in 24 fresh and 13 formalin-fixed, paraffin-embedded tissues of ICC and their corresponding normal parts. Microsatellite instability (MSI) was assessed in nDNA, using 12 highly polymorphic loci including 5 Bethesda markers. These loci were mainly related to major MMR genes, hMSH2 and hMLH1. Also 3 (C)n and/or (C)n(A)n repeat instability at 1 noncoding region in the displacement-loop (D-loop) and 2 coding sequences in NADH dehydrogenase subunit 1 and subunit 5 gene in mtDNA were analyzed. MSI was only detected in 1 (2.7%), 6 (16.7%), 1 (2.9%), 1 (2.9%) or 2 (6.3%) out of 37, 36, 35, 35 or 32 cases at BAT-25, D2S123, D3S1611, D11S904 or D17S250, respectively. LOH was found at D3S1298, D3S1561, D5S346 and TP53 in 4 (18.2%) out of 22, 2 (18.2%) out of 11, 6 (33.3%) out of 18 and 3 (12.5%) out of 24 informative cases, respectively. In mtDNA, none except a single case out of the 37 (2.7%) exhibited repeat sequence instability in the D-loop. We conclude that the liver fluke infection-associated ICC in Thailand is classified as low frequency MSI or microsatellite stable type and that DNA MMR system, through hMSH2 and hMLH1 gene mutations, does not play a major role in its carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer.

To define the involvement of p16/CDKN2 and p15/MTS2 tumor-suppressor genes for response to chemotherapy in primary epithelial ovarian cancer, we analyzed alterations of the gene in 45 patients who were treated with primary cytoreductive surgery followed by 6 courses of cis-diamminedichloroplatinum (II) (cisplatin)-based combination chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was found in 8 (18%) and 15 (33%) cases, respectively. Response to the chemotherapy was confirmed by finding at second surgery after the chemotherapy in 26 patients, resulting in 17 responders and 9 nonresponders. The abundance of gene deletion in nonresponders (56%) was significantly higher (p = 0.0463) when compared to that in responders (18%). Moreover, the deletion of genes was a significant poor prognostic factor (p = 0.0441) in advanced ovarian cancer. These results suggest that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for poor chemotherapy response and adverse prognosis in ovarian cancer patients.

Adult↗

PubMed2002

Troglitazone improves cardiac function in patients with congestive heart failure.

Troglitazone increased cardiac output and stroke volume, as a result of decreased peripheral resistance, in diabetic patients with normal cardiac function. The cardiovascular effects of troglitazone in patients with heart failure are unknown. The aim of the study was to evaluate the cardiovascular effects of troglitazone in patients with heart failure. Blood pressure and echocardiographic findings were evaluated before and 1, 2, 3 and 4 hours after a single dose of troglitazone (400 mg) or placebo, in eight type II diabetic patients with congestive heart failure. The plasma catecholamines and coefficient of variance of RR intervals (CVRR) were also measured. Neither heart rate nor blood pressure changed after the administration of troglitazone. Left ventricular (LV) end-diastolic dimension did not change either, however, the LV end-systolic dimension significantly decreased compared with its baseline value and with that of the placebo group. On the other hand, the % fractional shortening and the E/A ratio increased significantly after troglitazone. The LV end-diastolic volume did not change, whereas the LV end-systolic volume significantly decreased. The stroke volume and the LV ejection fraction significantly increased compared with its baseline value and with that of the placebo group. The peripheral vascular resistance did not change after the administration of troglitazone, whereas plasma catecholamines significantly decreased, and CVRR remained unchanged in both groups. These hemodynamic changes suggest that a single oral dose of troglitazone induced inotropy without activation of the sympathetic nervous system.

Blood Pressure↗

PubMed2002

Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure.

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

Adult↗