Biomedical subjects

Osamu Yamaguchi

Publications and source records attributed to Osamu Yamaguchi.

At least 19 recordsLinked to original sources

PubMed2006

Epidemiologic survey of lower urinary tract symptoms in Japan.

OBJECTIVES: A large-scale nationwide epidemiologic survey was performed to determine the prevalence of lower urinary tract symptoms (LUTS) and their impact on health-related quality of life (HRQOL) in Japan. METHODS: A self-administered questionnaire was mailed to 10,096 randomly selected Japanese men and women aged 40 years or older. The survey questions, developed by the Japan Neurogenic Bladder Society, encompassed four areas: demographic characteristics, LUTS, HRQOL, and treatment seeking. A modified King's Health Questionnaire was used to evaluate HRQOL. Correlations among the response scores were analyzed by Spearman's rank test. RESULTS: The responses from 4570 subjects (mean age 61 years) were analyzed. The prevalence rate for daytime urinary frequency of 8 and 11 times or more daily was 50% and 11%, respectively. The prevalence of nocturia occurring 1 and 3 or more times/night was 69% and 14%, respectively. For other symptom frequency (ie, weak urine flow, sensation of residual urine, bladder pain, urinary urgency, urgency incontinence, stress incontinence, and incontinence pad use), the prevalence rates ranged from 2% to 27% for 1 or more times/wk and 1% to 20% for 1 or more times/day. Emotions and sleep/energy were most affected by LUTS (10% each), followed by physical limitations (7%), role limitations (6%), social limitations (4%), and personal relationships (3%). Nocturia was most frequently (38%) reported to have the greatest impact on HRQOL. Of those who considered their daily life to be affected by LUTS, only 18% sought medical care. CONCLUSIONS: Although LUTS are highly prevalent in Japan, few subjects seek treatment. Greater awareness and understanding of LUTS is needed to manage symptoms and their consequences appropriately.

Adult↗

PubMed2006

Oxidative stress causes heart failure with impaired mitochondrial respiration.

Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O(2)(*)(-)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O(2)(*)(-) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.

Animals↗

PubMed2006

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

Animals↗

PubMed2006

Impaired growth of pancreatic exocrine cells in transgenic mice expressing human activin betaE subunit.

Activins, TGF-beta superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin beta subunit genes, betaC and betaE, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin betaE subunit. There were pronounced differences in the pancreata of the transgenic animals as compared with their wild-type counterparts. Pancreatic weight, expressed relative to total body weight, was significantly reduced. Histologically, adipose replacement of acini in the exocrine pancreas was observed. There was a significant decrease in the number of PCNA-positive cells in the acinar cells, indicating reduced proliferation in the exocrine pancreas of the transgenic mice. However, quantitative pancreatic morphometry showed that the total number and mass of the islets of the transgenic mice were comparable with those of the nontransgenic control mice. Our findings suggest a role for activin E in regulating the proliferation of pancreatic exocrine cells.

Animals↗

PubMed2006

A randomized comparative study of endocrine monotherapy and a combination of estramustine phosphate with the endocrine therapy in patients with untreated stage D prostate cancer.

BACKGROUND: We investigated the clinical efficacy and the prolongation of survival with combination therapy of estramustine phosphate (EMP) and endocrine therapy in untreated patients with progressive prostate cancer. METHODS: We randomly divided 57 patients with untreated stage D prostate cancer into two groups, an endocrine monotherapy group and a group receiving combination treatment, consisting of endocrine therapy plus EMP. Treatment was continued until deterioration. RESULTS: There were no significant differences in the improvement rating for subjective/objective symptoms or in progression-free survival between the two groups. However, overall survival was significantly prolonged in the combination therapy group (log-rank test, P = 0.0394; generalized Wilcoxon's test, P = 0.0145). In particular, overall survival was significantly prolonged, compared to that in the endocrine monotherapy group, in patients in the combination therapy group who were less than 74 years old, those with a performance status (PS) of 1 to 3, a pretreatment prostate-specific antigen (PSA) level of more than 20 ng/ml, moderately or poorly differentiated carcinoma, or a partial response (PR) based on the PSA level 12 weeks after the start of treatment. There was no significant difference in the incidence of side effects between the combination therapy and the endocrine monotherapy groups. CONCLUSION: A combination of EMP with endocrine therapy may be useful for initial treatment in younger patients (aged 73 or younger) and in patients at high risk of progressive prostate cancer.

Aged↗

PubMed2006

The promise of beta3-adrenoceptor agonists to treat the overactive bladder.

The detrusor muscle contains beta-adrenoceptors (beta-ARs), of which two subtypes--beta1-AR and beta2-AR--have been identified in most species. Although beta2-AR has an important role in muscle relaxation, evidence suggests that a third subtype--beta3-AR--mediates relaxation of human detrusor muscle. This article reviews the evidence for beta3-AR in human detrusor muscle and urothelium and discusses the potential use of beta3-AR agonists for the treatment of overactive bladder. In addition, the cAMP-dependent and -independent mechanisms of relaxation by way of beta-ARs in rat detrusor muscle, with and without pre-contraction, are reported. Finally, the consequences of mutation of a beta3-AR gene (relating to the pathophysiology of idiopathic detrusor instability) are discussed.

Adrenergic beta-3 Receptor Agonists↗

PubMed2006

Symptom assessment tool for overactive bladder syndrome--overactive bladder symptom score.

OBJECTIVES: Overactive bladder (OAB) is a common symptom syndrome with urgency, urinary frequency, and urgency incontinence. To collectively express OAB symptoms, we developed the overactive bladder symptom score (OABSS). METHODS: Four symptoms--daytime frequency, nighttime frequency, urgency, and urgency incontinence--were scored. The weighing score was based on a secondary analysis of an epidemiologic database. Psychometric properties were examined in five patient groups: OAB (n = 83), asymptomatic controls (n = 34), stress incontinence (n = 29), benign prostatic hyperplasia (n = 28), and other diseases with urinary symptoms (n = 26). RESULTS: The maximal score was defined as 2, 3, 5, and 5 for daytime frequency, nighttime frequency, urgency, and urgency incontinence, respectively. The sum score (OABSS 0 to 15) was significantly greater in the patients with OAB (8.36) than in the other patient groups (1.82 to 5.14). The distribution of the OABSS showed a clear separation between those with OAB and asymptomatic controls. The OABSS correlated positively with the individual scores (Spearman's r = 0.10 to 0.78) and quality-of-life scores assessed by the King's Health Questionnaire (Spearman's r = 0.20 to 0.49). The weighted kappa coefficients were 0.804 to 1.0 for each symptom score and 0.861 for OABSS. The posttreatment reduction in the OABSS was consistent with the global impression of patients of the therapeutic efficacy. CONCLUSIONS: The OABSS, the sum score of four symptoms (daytime frequency, nighttime frequency, urgency, and urgency incontinence), has been developed and validated. OABSS may be a useful tool for research and clinical practice.

Aged↗

PubMed2006

[Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (2004). III. Secular changes in susceptibility].

The bacteria (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa) isolated from patients diagnosed as urinary tract infections (UTIs) in 14 institutions in Japan were collected between August 2004 and July 2005. The susceptibilities of these bacteria to various antimicrobial agents were measured. The bacteria were divided into 2 groups consisting of uncomplicated UTIs and complicated UTIs (with and without indwelling catheter) based on their isolation origins. The results were compared with those obtained between 1995 and 2003. The drug sensitivity of S. aureus in this year was similar to those in up to the previous year and S. aureus showed the best susceptibility to vancomycin (VCM) and arbekacin (ABK). The drug sensitivity of E. faecalis in this year also was similar to those in up to the previous year. The susceptibility of E. coli to cephems in this year was generally good and was similar to those in up to the previous year. MIC90 of cefozopran (CZOP) was the most stable and 0.125 microg/mL or less since 1995. The susceptibility of E. coli to cefpirome (CPR) and cefotiam (CTM) also was good but to cefaclor (CCL), cefixime (CFIX), and cefpodoxime (CPDX) was largely decreased in complicated UTI groups. The sensitivity of E. coli to carbapenems also was good but to carumonam (CRMN) tended to decrease. The susceptibility of E. coli to quinolones, however, has largely changed and has decreased since 2003 in uncomplicated UTIs and 2000 in complicated UTIs. That was suggested the development of the resistance to the drug. The susceptibility of Klebsiella spp. to cefazolin (CEZ), CTM, CCL, CPDX, and cefditoren (CDTR) decreased in the previous year and recovered to the year before the previous year in this year. The susceptibility of Klebsiella spp. to other cephems was stable since 1995, especially against CZOP, the highest sensitivity (MIC90: < or = 0.125 microg/mL) was maintained. The susceptibility of Klebsiella spp. to carbapenems and CRMN also was good. The susceptibility of Klebsiella spp. to aminoglycosides was lower than to CZOP but was stable since 1995. The susceptibility of P. aeruginosa was generally low and has largely changed against the majority of the agents since 1995. The susceptibility of P. aeruginosa isolated from uncomplicated UTIs has largely changed against ceftazidime (CAZ), cefsulodin (CFS), CZOP, imipenem (IPM), meropenem (MEPM), aztreonam (AZT), CRMN, gentamicin (GM), and tobramycin (TOB). The susceptibility of P. aeruginosa isolated from complicated UTIs has largely changed against CSF, CZOP, MEPM, GM, and ciprofloxacin (CPFX). The susceptibility of P. aeruginosa isolated from complicated UTIs has been stable against amikacin (AMK). For annual changes in MIC50, TOB and IPM had a relatively stable and high activity (MIC50: 0.5-2 microg/mL).

Anti-Bacterial Agents↗

PubMed2005

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

Animals↗

PubMed2005

Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors.

We investigated the cAMP-dependent and -independent mechanisms of relaxation via beta-adrenoceptor in rat detrusor muscle with and without pre-contraction. A microdialysis technique was used to measure detrusor tension and cAMP level on the same detrusor tissue. In non-contracted tissue, isoproterenol, clenbuterol (beta2-adrenoceptor agonist) and FR165101, ((8S)-8-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy]acetic acid hydrochloride (beta3-adrenoceptor agonist) relaxed detrusor muscle and cAMP levels also increased in a concentration dependent manner. SQ22536 (adenylyl cyclase inhibitor) markedly suppressed relaxation, suggesting that beta-adrenoceptor-mediated relaxation may be attributed mainly to cAMP-dependent mechanism. In high K+ pre-contracted tissue, although relaxation advanced in a concentration dependent manner, cAMP production reached a plateau at concentrations of more than 10(-7) M. SQ22536 had only a small inhibitory effect. However, large-conductance, Ca2+-activated K+ (BK(Ca)) channel inhibitors, charybdotoxin and iberiotoxin markedly suppressed relaxation. These results suggest that in addition to cAMP-dependent pathway, BK(Ca) channels are involved in the beta-adrenoceptor agonists-induced relaxation in pre-contracted detrusor muscle.

Adenine↗

PubMed2005

Apoptosis signal-regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic cardiomyocyte death.

The molecular basis of myocardial cell death in the ischemia-reperfused heart still remains to be clarified. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We studied ASK1(-/-) mice to examine the role of ASK1 in ischemia-reperfusion injury. In the wild-type heart, ischemia-reperfusion resulted in necrotic injury, whereas infarct size was drastically reduced in the ASK1(-/-) heart. The necrotic injury was not accompanied with any evidence of apoptosis such as an increase in TUNEL-positive cells, DNA fragmentation or the activation of caspase-3. ASK1(-/-) cardiomyocytes were more resistant to H(2)O(2)- or Ca(2+)-induced apoptotic and non-apoptotic cell death compared with wild-type cells. These data suggest that ASK1 is involved in necrosis as well as apoptosis and that ASK1-dependent necrosis is likely to contribute to myocardial cell death in the ischemia-reperfused heart.

Animals↗

PubMed2005

The antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy.

The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is used to treat patients with ischemic brain damage. We and others reported previously that in vitro and in vivo reactive oxygen species (ROS) act as second messengers to develop cardiac hypertrophy. In this study, we used an in vivo murine model of pressure overload-induced cardiac hypertrophy to examine the effects of edaravone on left ventricular hypertrophy. The animals were subjected to the transverse thoracic aorta constriction, and edaravone (10 mg/kg) was infused intraperitoneally twice daily. Seven days after the operation, we observed a significant increase in ROS production in hearts, which was eliminated by the treatment with edaravone. Pressure-overloaded hearts showed a significant increase in left ventricular weight/body weight ratio and the expression level of atrial natriuretic factor mRNA, which were attenuated by edaravone. It also reduced perivascular and intermuscular fibrosis and inhibited pressure overload-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream kinases of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase. Edaravone attenuated the hypertrophic response even when the treatment was started after the onset of cardiac hypertrophic response. These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway.

Animals↗

PubMed2005

Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.

Mitochondria play an important role in energy production, Ca2+ homeostasis and cell death. In recent years, the role of the mitochondria in apoptotic and necrotic cell death has attracted much attention. In apoptosis and necrosis, the mitochondrial permeability transition (mPT), which leads to disruption of the mitochondrial membranes and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. We therefore created mice lacking cyclophilin D (CypD), a protein considered to be involved in the mPT, to analyse its role in cell death. CypD-deficient mice were developmentally normal and showed no apparent anomalies, but CypD-deficient mitochondria did not undergo the cyclosporin A-sensitive mPT. CypD-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload. In addition, CypD-deficient mice showed a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Our results indicate that the CypD-dependent mPT regulates some forms of necrotic death, but not apoptotic death.

Animals↗

PubMed2005

CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy.

Ca2+/calmodulin-dependent protein kinase (CaMK) is an important downstream target of Ca2+ in the hypertrophic signaling pathways. We previously showed that the activation of apoptosis signal-regulating kinase 1 (ASK1) or NF-kappaB is sufficient for cardiomyocyte hypertrophy. Infection of isolated neonatal cardiomyocytes with an adenoviral vector expressing CaMKIIdelta3 (AdCaMKIIdelta3) induced the activation of ASK1, while KN93, an inhibitor of CaMKII, inhibited phenylephrine-induced ASK1 activation. Overexpression of CaMKIIdelta3 induced characteristic features of in vitro cardiomyocyte hypertrophy. Infection of cardiomyocytes with an adenoviral vector expressing a dominant negative mutant of ASK1 (AdASK(KM)) inhibited the CaMKIIdelta3-induced hypertrophic responses. Overexpression of CaMKIIdelta3 increased the kappaB-dependent promoter/luciferase activity and induced IkappaBalpha degradation. Coinfection with AdCaMKIIdelta3 and AdASK(KM), and pre-incubation with KN93 attenuated CaMKIIdelta3- and phenylephrine-induced NF-kappaB activation, respectively. Expression of a degradation resistant mutant of IkappaBalpha inhibited CaMKIIdelta3-induced hypertrophic responses. These results indicate that CaMKIIdelta3 induces cardiomyocyte hypertrophy mediated through ASK1-NF-kappaB signal transduction pathway.

Animals↗

PubMed2005

A case of interstitial cystitis accompanying Sjögren's syndrome.

A 51-year-old woman with interstitial cystitis was referred for screening of autoimmune disease. She was positive for results of Schirmer and Saxon tests and for ss/A and ss/B antibodies. Autoantibodies to type 3 muscarinic acetylcholine receptor were detected in the patient's serum by Western blotting. We diagnosed her as having interstitial cystitis accompanying Sjögren's syndrome. To enable early treatment, interstitial cystitis should be considered when patients with Sjögren's syndrome complain of urinary symptoms.

Journal Article↗

PubMed2005

An epidemiological survey of overactive bladder symptoms in Japan.

OBJECTIVE: To report an epidemiological survey of lower urinary tract symptoms (LUTS) to determine the prevalence of overactive bladder (OAB) symptoms (defined as a symptom complex of daily urinary frequency of eight or more times and urgency once or more per week) in Japan. SUBJECTS AND METHODS: A self-administered questionnaire was mailed to 10,096 Japanese men and women aged > or = 40 years selected by a two-stage randomized process. Survey questions, developed by members of the Japan Neurogenic Bladder Society Committee, covered four areas: demographic characteristics, LUTS, health-related quality of life (HRQoL), and hospital attendance. RESULTS: The responses from 4570 respondents (mean age 61 years) were analysed. The estimated prevalence of OAB was 12.4% (men 14%, women 11%). Prevalence rates for OAB with and without urgency incontinence (one or more episode/week) were 6.4% and 6.0%, respectively. Prevalence rates increased with age; 5% of respondents aged 40-49 and 37% of those aged > or = 80 years had OAB. HRQoL was compromised in 53% of respondents with OAB symptoms, specifically emotions (42%), sleep/vitality (37%), physical limitation (34%), role limitation (29%), and social limitation (22%). Among those whose HRQoL was affected, 23% (men 36%, women 8%) had visited a medical institution because of their urinary problems. CONCLUSION: The results from this survey indicate that the prevalence of OAB was high and increased with age, but the rate of hospital attendance was low. Public awareness of OAB should be increased so that there can be optimum management of this condition.

Adult↗

PubMed2005

[Correlation between re-biopsy one year after endocrine therapy and long-term prognosis in localized prostate cancer].

PURPOSE: Even in the cases of localized prostate cancer, there are a substantial number of patients who undergo endocrine therapy, and their prognosis is affected by the treatment. We evaluated the histological effect of endocrine therapy and analyzed its correlation with prognosis. METHODS AND SUBJECTS: Seventy-seven cases with localized prostate cancer who underwent maximal androgen blockade (MAB) therapy 1 year or longer were pathologically evaluated using repeat biopsy specimens from November 1994 to October 2001. The relationship between clinical parameters and histological effect in repeat biopsy specimens was examined. Biopsy was conducted mainly by the 6-site systematic method, and the histological effect was judged in accordance with the General Rules for Clinical and Pathological Study of Prostate Cancer (3rd edition). The median re-biopsy and follow-up periods were 13 months and 41 months, respectively. RESULTS: Using this criteria for the histological effects of anti-cancer treatment, the histological effect of endocrine therapy was most frequently observed in class G3b with 61.0%, and correlations with PSA nadir and initial biopsy positive number before endocrine therapy were observed. After biopsy, radical prostatectomy was performed on 9 patients (endocrine therapy was concurrently performed on 4), endocrine therapy on 67 (intermittent administration on 21), and radiation therapy on 1 (MAB was concurrently performed). Outcomes included PSA failure in 14, of whom 2 died of cancer. Three-year and 5-year PSA-failure free survival rates were 91.1% and 76.3%, respectively. Pathological disease stage in radical prostatectomy specimens was examined by dividing it into class G0-2 and class G0-3. This revealed a significant correlation between histological effect and pathological disease stage (pT2-3). PSA-failure free survival was analyzed in 67 of the 77 patients who underwent endocrine therapy. A significantly large number of PSA-failures occurred in class G0-2. Multivariate analysis revealed that the histological effect alone was the influencing factor in PSA-failure. CONCLUSION: A strong histological effect by MAB 1 year or longer after treatment was observed on localized prostate cancer. Evaluation of the histological effect by the present method was considered to be a useful predictor for organ-confined disease after radical prostatectomy and endocrine therapy for PSA-failure.

Aged↗

PubMed2004

Pressure overload induces cardiac dysfunction and dilation in signal transducer and activator of transcription 6-deficient mice.

BACKGROUND: Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6-/-) mice to examine the in vivo role of STAT6. METHODS AND RESULTS: STAT6-/- hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6-/- mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling-positive myocytes after TAC had increased in STAT6-/- compared with wild-type mice. Prolonged induction of tumor necrosis factor-alpha (TNF-alpha) mRNA was observed in STAT6-/- hearts, whereas TNF-alpha mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6-/- mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6-/- cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6-/- cardiomyocytes was rescued by forced expression of STAT6. CONCLUSIONS: STAT6 plays a protective role against hemodynamic stress in hearts.

Animals↗