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1.
Nervenarzt ; 91(9): 799-807, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32642947

RESUMO

BACKGROUND: It is common practice to inform patients about causes and treatment models when starting psychiatric treatment or psychotherapy for schizophrenia. However, previous research indicates that focusing on etiological models increases stigmatizing beliefs. This raises the question of whether contemporary, medical or cognitive behavioral therapy (CBT)-based treatment models share this negative side effect. AIM: This experiment tested whether providing information about medical vs. CBT-based vs. combined treatment models affects stigmatizing attitudes towards schizophrenia and the expected efficacy of these treatments. METHODS: Participants received a case vignette of a person with schizophrenia including either: (1) no treatment details, or a description of treatment with (2) medication, (3) CBT, or (4) medication and CBT. Next, stigmatizing attitudes (stereotypes, affective reactions, and desired social distance) were assessed and participants rated the perceived effectiveness of different treatment methods. RESULTS: No treatment model showed an effect on stigmatizing attitudes. Medical and CBT treatment information (alone or in combination) had a positive effect on subjective efficacy ratings for the respective treatment. CONCLUSION: There appear to be no negative side effects of (biogenetic) models when presented in a context emphasizing recovery. Moreover, medication and CBT treatment information showed additive positive effects on the rating of treatment strategies. A combined treatment model integrating various evidence-based methods appears to be most useful in clinical practice.


Assuntos
Esquizofrenia , Humanos , Motivação , Esquizofrenia/diagnóstico , Esquizofrenia/terapia , Estigma Social , Estereotipagem
2.
Acta Psychiatr Scand ; 138(2): 133-144, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29667181

RESUMO

OBJECTIVE: We tested whether people with schizophrenia and prominent expressive negative symptoms (ENS) show reduced facial expressions in face-to-face social interactions and whether this expressive reduction explains negative social evaluations of these persons. METHOD: We compared participants with schizophrenia with high ENS (n = 18) with participants with schizophrenia with low ENS (n = 30) and with healthy controls (n = 39). Participants engaged in an affiliative role-play that was coded for the frequency of positive and negative facial expression and rated for social performance skills and willingness for future interactions with the respective role-play partner. RESULTS: Participants with schizophrenia with high ENS showed significantly fewer positive facial expressions than those with low ENS and controls and were also rated significantly lower on social performance skills and willingness for future interactions. Participants with schizophrenia with low ENS did not differ from controls on these measures. The group difference in willingness for future interactions was significantly and independently mediated by the reduced positive facial expressions and social performance skills. CONCLUSION: Reduced facial expressiveness in schizophrenia is specifically related to ENS and has negative social consequences. These findings highlight the need to develop aetiological models and targeted interventions for ENS and its social consequences.


Assuntos
Expressão Facial , Esquizofrenia/diagnóstico , Sorriso/psicologia , Adulto , Emoções/fisiologia , Feminino , Humanos , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Esquizofrenia/epidemiologia , Habilidades Sociais
3.
Psychol Med ; 48(8): 1299-1307, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28956520

RESUMO

BACKGROUND: Cognitive models postulate that negative-self-schemas (NSS) cause and maintain positive symptoms and that negative affect mediates this link. However, only few studies have tested the temporal mediation claim systematically using an appropriate design. METHODS: A longitudinal cohort design in an online community sample (N = 962) from Germany, Indonesia, and the USA was used. NSS, negative affect and positive symptoms were measured at four time-points (T0-T3) over a 1-year period. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the temporal mediation. RESULTS: Independent cross-lagged panel models showed a significant unidirectional longitudinal path from NSS to positive symptoms (T2-T3, ß = 0.18, p < 0.01) and bidirectional longitudinal associations from NSS to negative affect (T0-T1, γ = 0.14, p < 0.01) and vice versa (T0-T1, γ = 0.19, p < 0.01). There was also a significant indirect pathway from NSS at baseline via negative affect at T1 and T2 to positive symptoms at T3 (unstandardized indirect effect coefficient = 0.020, p < 0.05, BCa CI 0.004-0.035), indicating mediation. CONCLUSIONS: Our findings support the postulated affective pathway from NSS to positive symptoms via negative affect. Specifically, our data indicate that NSS and negative affect influence each other and build up over the course of several months before leading on to positive symptoms. We conclude that interrupting this process by targeting NSS and negative affect early in the process could be a promising strategy to prevent the exacerbation of positive symptoms.


Assuntos
Afeto , Ansiedade/psicologia , Depressão/psicologia , Transtornos Psicóticos/psicologia , Autoimagem , Adolescente , Adulto , Idoso , Feminino , Alemanha , Humanos , Indonésia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Escalas de Graduação Psiquiátrica , Análise de Regressão , Inquéritos e Questionários , Estados Unidos , Adulto Jovem
4.
Eur Psychiatry ; 43: 14-18, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28365463

RESUMO

BACKGROUND: Internet gaming disorder (IGD) has been included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Currently, associations between IGD in early adolescence and mental health are largely unexplained. In the present study, the relation of IGD with adolescent and parental mental health was investigated for the first time. METHODS: We surveyed 1095 family dyads (an adolescent aged 12-14 years and a related parent) with a standardized questionnaire for IGD as well as for adolescent and parental mental health. We conducted linear (dimensional approach) and logistic (categorical approach) regression analyses. RESULTS: Both with dimensional and categorical approaches, we observed statistically significant associations between IGD and male gender, a higher degree of adolescent antisocial behavior, anger control problems, emotional distress, self-esteem problems, hyperactivity/inattention and parental anxiety (linear regression model: corrected R2=0.41, logistic regression model: Nagelkerke's R2=0.41). CONCLUSIONS: IGD appears to be associated with internalizing and externalizing problems in adolescents. Moreover, the findings of the present study provide first evidence that not only adolescent but also parental mental health is relevant to IGD in early adolescence. Adolescent and parental mental health should be considered in prevention and intervention programs for IGD in adolescence.


Assuntos
Comportamento Aditivo/diagnóstico , Internet , Saúde Mental , Pais/psicologia , Jogos de Vídeo/psicologia , Adolescente , Comportamento Aditivo/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Autoimagem , Fatores Sexuais , Estresse Psicológico/psicologia
5.
Eur Psychiatry ; 42: 111-119, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28364686

RESUMO

BACKGROUND: The causal role of childhood trauma for psychosis is well established, but the mechanisms that link trauma to psychosis are largely unknown. Since childhood trauma is known to cause difficulties in emotion regulation (ER) and patients with psychosis show impaired ER, we hypothesize that impaired ER explains why people with a background of trauma are prone to psychotic experiences. METHODS: The study used a longitudinal cohort design based on a community sample (N=562) from Germany, Indonesia, and the United States. Childhood trauma was assessed at baseline. ER and psychotic experiences (defined as positive symptom frequency and related distress) were measured repeatedly at a 4-, 8-, and 12-month follow-up. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the predictive value of ER on psychotic experiences and its mediating role in the association of childhood trauma and psychotic experiences. RESULTS: The cross-lagged paths from impaired ER to symptom distress (but not frequency) were significant. However, there was also evidence for the reverse causation from symptom frequency and distress to impaired ER. ER partially mediated the significant prospective paths from childhood trauma to symptom distress. CONCLUSION: The findings demonstrate that ER plays a role in translating childhood trauma into distressing psychotic experiences in later life. Moreover, the findings point to a maintenance mechanism in which difficulties in ER and symptom distress exacerbate each other. Thus, ER could be a promising target for interventions aimed at prevention of psychosis.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Maus-Tratos Infantis/psicologia , Transtornos Psicóticos/epidemiologia , Estresse Psicológico/epidemiologia , Adulto , Sobreviventes Adultos de Maus-Tratos Infantis/estatística & dados numéricos , Criança , Maus-Tratos Infantis/estatística & dados numéricos , Emoções , Feminino , Alemanha , Humanos , Masculino , Estudos Prospectivos , Transtornos Psicóticos/psicologia , Fatores de Risco , Estresse Psicológico/psicologia
6.
Eur Psychiatry ; 38: 31-39, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27642702

RESUMO

BACKGROUND: The general efficacy of cognitive behavior therapy for psychosis (CBTp) is well established. Although guidelines recommend that CBTp should be offered over a minimum of 16 sessions, the minimal number of sessions required to achieve significant changes in psychopathology has not been systematically investigated. Empirically informed knowledge of the minimal and optimal dose of CBTp is relevant in terms of dissemination and cost-effectiveness. METHODS: We approached the question of what constitutes an appropriate dose by investigating the dose (duration of CBTp)×response (symptomatic improvement) relationship for positive symptoms, negative symptoms and depression. Patients with psychotic disorders (n=58) were assessed over the course of 45 sessions of CBTp in a clinical practice setting. At baseline and after session 5, 15, 25, and 45, general psychopathology, psychotic symptoms, symptom distress and coping were assessed with self-report questionnaires. Additionally, individually defined target symptoms and coping were assessed after each session. RESULTS: Significant symptom improvement and reduction of symptom distress took place by session 15, and stayed fairly stable thereafter. The frequency of positive and negative symptoms reached a minimum by session 25. CONCLUSIONS: Our findings support recommendations to provide CBTp over a minimum of 16 sessions and indicate that these recommendations are generalizable to clinical practice settings. However, the findings also imply that 25 sessions are the more appropriate dose. This study contributes to an empirically informed discussion on the minimal and optimal dose of CBTp. It also provides a basis for planning randomized trials comparing briefer and longer versions of CBTp.


Assuntos
Terapia Cognitivo-Comportamental/estatística & dados numéricos , Transtorno Depressivo/terapia , Transtornos Psicóticos/terapia , Adaptação Psicológica , Adulto , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Satisfação do Paciente , Psicopatologia , Transtornos Psicóticos/psicologia , Ajustamento Social , Resultado do Tratamento
7.
Psychol Med ; 46(10): 2179-88, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27269768

RESUMO

BACKGROUND: A considerable proportion of people with schizophrenia spectrum disorders do not take antipsychotic medication but seem to be functioning well. However, little is known about this group. To test the assumption that absence of medication is compensated for by more effective coping and increased social support, this study compared symptoms, functioning, coping strategies and social support in non-medicated and medicated individuals with schizophrenia spectrum disorders. METHOD: In all, 48 participants with a DSM-IV schizophrenia spectrum disorder who were taking (n = 25) or not taking antipsychotic medication (n = 23) were included. Assessment consisted of self-ratings of symptoms, symptom-related distress and social support combined with a semi-structured interview that assessed general and social functioning, subjective evaluation of symptoms and coping strategies. RESULTS: Symptom severity and distress did not differ between the groups. However, the non-medicated participants had significantly higher levels of general functioning than medicated participants and a longer duration of being non-medicated was significantly associated with a higher level of general functioning. In contrast to the hypotheses, not taking medication was not associated with more effective coping strategies or with higher levels of social support. Medicated participants more frequently reported the use of professional help as a coping strategy. CONCLUSIONS: Our results corroborate previous studies finding improved functioning in individuals with schizophrenia spectrum disorders who do not take medication compared with those who take medication, but do not support the notion that this difference is explicable by better coping or higher levels of social support. Alternative explanations and avenues for research are discussed.


Assuntos
Adaptação Psicológica/fisiologia , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Apoio Social , Adulto , Feminino , Humanos , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade
9.
Psychol Med ; 39(11): 1821-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19426569

RESUMO

BACKGROUND: Cognitive biases, especially jumping to conclusions (JTC), are ascribed a vital role in the pathogenesis of schizophrenia. This study set out to explore motivational factors for JTC using a newly developed paradigm. METHOD: Twenty-seven schizophrenia patients and 32 healthy controls were shown 15 classical paintings, divided into three blocks. Four alternative titles (one correct and three lure titles) had to be appraised according to plausibility (0-10). Optionally, participants could decide for one option and reject one or more alternatives. In random order across blocks, anxiety-evoking music, happy music or no music was played in the background. RESULTS: Patients with schizophrenia, particularly those with delusions, made more decisions than healthy subjects. In line with the liberal acceptance (LA) account of schizophrenia, the decision threshold was significantly lowered in patients relative to controls. Patients were also more prone than healthy controls to making a decision when the distance between the first and second best alternative was close. Furthermore, implausible alternatives were judged as significantly more plausible by patients. Anxiety-evoking music resulted in more decisions in currently deluded patients relative to non-deluded patients and healthy controls. CONCLUSIONS: The results confirm predictions derived from the LA account and assert that schizophrenia patients decide hastily under conditions of continued uncertainty. The fact that mood induction did not exert an overall effect could be due to the explicit nature of the manipulation, which might have evoked strategies to counteract their influence.


Assuntos
Afeto , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Tomada de Decisões , Comportamento Impulsivo/diagnóstico , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Incerteza , Adulto , Ansiedade/psicologia , Delusões/diagnóstico , Delusões/psicologia , Feminino , Felicidade , Humanos , Comportamento Impulsivo/psicologia , Masculino , Rememoração Mental , Pessoa de Meia-Idade , Música , Reconhecimento Visual de Modelos , Escalas de Graduação Psiquiátrica , Adulto Jovem
10.
Nervenarzt ; 80(3): 329-39, 2009 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-19242670

RESUMO

BACKGROUND: Some studies revealed that psychiatrists have more negative attitudes than psychologists towards patients with schizophrenia. This raises the question of whether different models of the aetiology of schizophrenia and the amount of personal contact influence the attitudes of mental health professionals. SAMPLE AND METHODS: Explicit and implicit attitudes towards schizophrenia were assessed in medical and psychology students (n=60 and n=61, respectively) as well as their familiarity with the disorder and their subjective models of its aetiology. RESULTS: Medical and psychology students showed a substantial level of negative attitudes. Personal contact was negatively associated with stereotypes among medical students and positively associated among psychology students. Positive attitudes were related to biogenetic causal beliefs among medical students and to psychosocial causal beliefs among psychology students. CONCLUSIONS: The results emphasise the need to adapt antistigma campaigns to target groups. They also indicate the superiority of a multidimensional aetiology over monocausal aetiological models in reducing stigma.


Assuntos
Atitude do Pessoal de Saúde , Educação de Graduação em Medicina/estatística & dados numéricos , Médicos/estatística & dados numéricos , Psicologia/estatística & dados numéricos , Esquizofrenia , Alemanha , Humanos , Pacientes
11.
Psychol Med ; 39(7): 1129-39, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18940024

RESUMO

BACKGROUND: Vulnerability-stress models ascribe stress a pivotal role in the development of psychosis. However, moderating and mediating mechanisms translating stress into psychosis and the specificity of the association are not clearly established. It is hypothesized that stress will trigger paranoid ideation in vulnerable individuals through an increase in negative emotion. METHOD: Using a repeated-measures design, 64 healthy participants with varying levels of vulnerability [psychosis symptoms assessed by the Community Assessment of Psychic Experiences (CAPE)] were assigned to a stress and a non-stress condition in random order. Stress was induced by exposing participants to building-site noise (75 dB) applied concurrently with difficult knowledge questions. Symptoms of paranoia, depression and obsessive compulsive disorder (OCD) were assessed by state-adapted versions of clinical scales. RESULTS: In the stress condition there was an increase in paranoia, depression and negative emotion. Multilevel linear modeling (MLM) revealed the increase in paranoia under stress to be moderated by the level of vulnerability and mediated by anxiety. Although participants generally showed an increase in anxiety under stress, anxiety was more strongly related to paranoia in participants with higher baseline symptomatology. CONCLUSIONS: The results support and specify the role of emotional reactions to stressors on the pathway from vulnerability to psychosis and highlight the relevance of anxiety.


Assuntos
Transtornos Paranoides/psicologia , Estresse Psicológico/complicações , Adolescente , Adulto , Afeto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/psicologia , Nível de Alerta , Atenção , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/psicologia , Diagnóstico Diferencial , Feminino , Alemanha , Humanos , Masculino , Ruído/efeitos adversos , Transtornos Paranoides/diagnóstico , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Psicometria , Esquizofrenia Paranoide/diagnóstico , Esquizofrenia Paranoide/psicologia , Adulto Jovem
12.
Schizophr Res ; 96(1-3): 232-45, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17826034

RESUMO

Psychoeducation (PE) for schizophrenia and other psychotic disorders is widely adopted but insufficiently evaluated. So far, meta-analytic data has demonstrated efficacy for PE when interventions include family members. Whether PE directed solely at patients is also effective remains unclear. The current meta-analysis evaluates short- and long-term efficacy of PE with and without inclusion of families with regard to relapse, symptom-reduction, knowledge, medication adherence, and functioning. Randomized controlled trials comparing PE to standard care or non-specific interventions were included. A literature search in the Cochrane Library, PsycINFO and Medline retrieved 199 studies for closer examination, of which 18 studies, reporting on 19 comparisons, met the inclusion criteria. These studies were coded with regard to methodology, participants, interventions and validity. Effect sizes were integrated using the fixed effects model for homogeneous effects and the random effects model for heterogeneous effects. Independent of treatment modality, PE produced a medium effect at post-treatment for relapse and a small effect size for knowledge. PE had no effect on symptoms, functioning and medication adherence. Effect sizes for relapse and rehospitalization remained significant for 12 months after treatment but failed significance for longer follow-up periods. Interventions that included families were more effective in reducing symptoms by the end of treatment and preventing relapse at 7-12 month follow-up. Effects achieved for PE directed at patients alone were not significant. It is concluded that the additional effort of integrating families in PE is worthwhile, while patient-focused interventions alone need further improvement and research.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/terapia , Humanos , Seleção de Pacientes , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Recidiva , Sensibilidade e Especificidade , Resultado do Tratamento
13.
Nervenarzt ; 77(5): 576-86, 2006 May.
Artigo em Alemão | MEDLINE | ID: mdl-15944853

RESUMO

BACKGROUND: The aim of this study was to assess the potential for future violent behaviour comparing patients recruited from forensic and general psychiatric wards in Germany. PATIENTS AND METHODS: Fifty patients were recruited from a forensic hospital and 29 from a general psychiatric hospital. In the weeks preceding discharge, structured assessments of the future risk of violent behaviour were completed using the HCR-20. RESULTS: There was little difference in the risk presented by the two groups. Forensic patients presented an elevated risk of violence because of historical factors, while the risk among patients from general psychiatry was due to clinical symptoms. CONCLUSION: Some criminal offences could be prevented if more time and effort were spent in general psychiatric practice in identifying patients at high risk for violence and in reducing symptoms of psychoses before discharge.


Assuntos
Psiquiatria Legal/métodos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Determinação da Personalidade/estatística & dados numéricos , Psiquiatria/métodos , Medição de Risco/métodos , Violência/estatística & dados numéricos , Alemanha/epidemiologia , Humanos , Incidência , Fatores de Risco , Violência/prevenção & controle , Violência/psicologia
14.
J Membr Biol ; 187(2): 157-65, 2002 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12029372

RESUMO

K-Cl cotransport is activated by vasodilators in erythrocytes and vascular smooth muscle cells and its regulation involves putative kinase/phosphatase cascades. N-ethylmaleimide (NEM) activates the system presumably by inhibiting a protein kinase. Nitrovasodilators relax smooth muscle via cGMP-dependent activation of protein kinase G (PKG), a regulator of membrane channels and transporters. We investigated whether PKG regulates K-Cl cotransport activity or mRNA expression in normal, PKG-deficient-vector-only-transfected (PKG-) and PKG-catalytic-domain-transfected (PKG+) rat aortic smooth muscle cells. K-Cl cotransport was calculated as the Cl-dependent Rb influx, and mRNA was determined by semiquantitative RT-PCR. Baseline K-Cl cotransport was higher in PKG+ than in PKG- cells (p <0.01). At 0.5 mM, NEM stimulated K-Cl cotransport by 5-fold in PKG- but not in PKG+ cells. However, NEM was more potent although less effective to activate K-Cl cotransport in normal (passage 1-3) and PKG+ than in PKG- cells. In PKG- cells, [(dihydroindenyl) oxy] alkanoic acid (300 mM) but not furosemide (1 mM) inhibited K-Cl cotransport. Furthermore, no difference in K-Cl cotransport mRNA expression was observed between these cells. In conclusion, this study shows that manipulation of PKG expression in vascular smooth muscle cells affects K-Cl cotransport activity and its activation by NEM.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Etilmaleimida/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Simportadores/metabolismo , Acetatos/farmacologia , Animais , Aorta/citologia , Células Cultivadas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Etilmaleimida/farmacologia , Furosemida/farmacologia , Regulação da Expressão Gênica/fisiologia , Indenos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Simportadores/antagonistas & inibidores , Simportadores/genética
15.
J Appl Physiol (1985) ; 91(3): 1421-30, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11509544

RESUMO

cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Músculo Liso/metabolismo , Transdução de Sinais/fisiologia , Animais , Expressão Gênica/fisiologia , Tono Muscular/fisiologia , Óxido Nítrico/metabolismo
16.
J Biol Chem ; 276(24): 21046-52, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11274213

RESUMO

K-Cl cotransport (KCC) is activated by nitric oxide donors and appears to be regulated by the cGMP signaling pathway. Expression of KCC mRNAs (KCC1-KCC4) in rat vascular smooth muscle cells (VSMCs) is unknown. We have reported the presence of KCC1 and KCC3 mRNAs in primary cultures of VSMCs by specific reverse transcription-polymerase chain reaction. KCC2 mRNA appeared at extremely low levels. KCC4 mRNA was undetectable. Semiquantitative reverse transcription-polymerase chain reaction revealed a 2:1 KCC1/KCC3 mRNA ratio in VSMCs. Depletion of protein kinase G (PKG)-1 from VSMCs did not change KCC3 mRNA expression. Analogous results were obtained with PKG-1-catalytic domain- and vector only-transfected VSMCs lacking endogenous PKG, suggesting no involvement of PKG-1 in the maintenance of basal KCC3 mRNA expression. However, 8-bromo-cGMP, a PKG stimulator, acutely increased KCC3 mRNA expression in a concentration- and time-dependent fashion; this effect was blocked by the PKG inhibitor KT5823 but not by actinomycin D. These findings show that VSMCs express mainly two mRNA isoforms, KCC1 and KCC3, and suggest that PKG participates post-transcriptionally in the acute KCC3 mRNA regulation. The role of KCC3 on cell volume and electrolyte homeostasis in response to PKG modulators remains to be determined.


Assuntos
Carbazóis , Proteínas de Transporte/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Regulação da Expressão Gênica/fisiologia , Indóis , Músculo Liso Vascular/metabolismo , Simportadores , Transcrição Genética , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Alcaloides/farmacologia , Animais , Aorta , Encéfalo/metabolismo , Domínio Catalítico , Células Cultivadas , Proteínas Quinases Dependentes de GMP Cíclico/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Cinética , Músculo Liso Vascular/citologia , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética/efeitos dos fármacos , Transfecção
17.
Arterioscler Thromb Vasc Biol ; 20(10): 2192-7, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11031203

RESUMO

Arterial smooth muscle cells undergo phenotypic and proliferative changes in response to balloon catheter injury. Nitric oxide (NO) and cGMP have been implicated in the inhibition of vascular smooth muscle cell proliferation and phenotypic modulation in cultured-cell studies. We have examined the expression of the major cGMP receptor protein in smooth muscle, cGMP-dependent protein kinase I (PKG), in response to balloon catheter injury in the swine coronary artery. On injury, there was a transient decrease in the expression of PKG in neointimal smooth muscle cells when compared with medial smooth muscle cells. The decrease in PKG expression was observed in the population of proliferating cells expressing the extracellular matrix protein osteopontin but not in cells present in the uninjured portion of the media. Coincident with the suppression of PKG expression in neointimal cells after injury, there was a marked increase in the expression of type II NO synthase (inducible NOS [iNOS], NOS-II) in the neointimal cells. These results suggest that PKG expression is transiently reduced in response to injury in the population of coronary arterial smooth muscle cells that are actively proliferating and producing extracellular matrix proteins. The reduction in PKG expression is also correlated temporally with increases in inflammatory activity in the injured vessels as assessed by iNOS expression. Coupled with our current knowledge regarding the role of PKG in the regulation of cultured cell phenotypes, these results imply that PKG may also regulate phenotypic modulation of vascular smooth muscle cells in vivo as well.


Assuntos
Vasos Coronários/lesões , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Músculo Liso Vascular/metabolismo , Angioplastia com Balão , Animais , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Autopsia , Western Blotting , Cateterismo , Divisão Celular , Células Cultivadas , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Regulação para Baixo , Proteínas da Matriz Extracelular/metabolismo , Humanos , Imuno-Histoquímica , Modelos Animais , Músculo Liso Vascular/patologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Coloração e Rotulagem , Suínos , Fatores de Tempo , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Cicatrização
18.
J Biol Chem ; 275(43): 33536-41, 2000 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-10922374

RESUMO

Many signal transduction pathways are mediated by the second messengers cGMP and cAMP, cGMP- and cAMP-dependent protein kinases (cGK and PKA), phosphodiesterases, and ion channels. To distinguish among the different cGMP effectors, inhibitors of cGK and PKA have been developed including the K-252 compound KT5823 and the isoquinolinesulfonamide H89. KT5823, an in vitro inhibitor of cGK, has also been used in numerous studies with intact cells to implicate or rule out the involvement of this protein kinase in a given cellular response. However, the efficacy and specificity of KT5823 as cGK inhibitor in intact cells or tissues have never been demonstrated. Here, we analyzed the effects of both KT5823 and H89 on cyclic-nucleotide-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in intact human platelets and rat mesangial cells. These two cell types both express high levels of cGK. KT5823 inhibited purified cGK. However, with both intact human platelets and rat mesangial cells, KT5823 failed to inhibit cGK-mediated serine 157 and serine 239 phosphorylation of VASP induced by nitric oxide, atrial natriuretic peptide, or the membrane-permeant cGMP analog, 8-pCPT-cGMP. KT5823 enhanced 8-pCPT-cGMP-stimulated VASP phosphorylation in platelets and did not inhibit forskolin-stimulated VASP phosphorylation in either platelets or mesangial cells. In contrast H89, an inhibitor of both PKA and cGK, clearly inhibited 8-pCPT-cGMP and forskolin-stimulated VASP phosphorylation in the two cell types. The data indicate that KT5823 inhibits purified cGK but does not affect a cGK-mediated response in the two different cell types expressing cGK I. These observations indicate that data that interpret the effects of KT5823 in intact cells as the major or only criteria supporting the involvement of cGK clearly need to be reconsidered.


Assuntos
Alcaloides/farmacologia , Plaquetas/enzimologia , Carbazóis , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mesângio Glomerular/enzimologia , Indóis , Sulfonamidas , Animais , Bovinos , Moléculas de Adesão Celular/metabolismo , Colforsina/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Humanos , Isoquinolinas/farmacologia , Proteínas dos Microfilamentos , Óxido Nítrico/fisiologia , Fosfoproteínas/metabolismo , Fosforilação , Ratos
19.
J Pharmacol Exp Ther ; 291(3): 967-75, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10565812

RESUMO

We previously showed that stimulation of cGMP-dependent protein kinase (PKG) stimulates L-type calcium current in newborn but not in adult rabbit ventricular myocytes. We have now isolated rabbit PKG type Ialpha cDNA (+1 to 2095), determined the sequence, and analyzed specific expression of PKG in adult and newborn rabbit heart by Western and Northern analyses to elucidate the developmental decline in the significance of PKG in cardiac function. We obtained full-length cDNA of PKG Ialpha from newborn rabbit heart mRNA with reverse transcription-polymerase chain reaction. The coding region of rabbit PKG Ialpha showed 94% homology to sequences of human and bovine PKG Ialpha. The deduced amino acid sequence of 671 amino acids showed seven substitutions between rabbit and either human or bovine PKG Ialpha. The major substitutions were found in the cGMP-binding domain. The cloned PKG 1alpha cDNA was expressed in COS cells. Expressed PKG showed cGMP stimulated PKG activity and immunoreactivity. Northern blot analysis of cardiac tissue demonstrated PKG Ialpha mRNA of 6.8 kb, with much higher levels in newborn than in adult cells. Western analysis in homogenates from ventricular tissues and isolated ventricular myocytes of rabbit heart showed much higher expression of PKG type I protein in newborn compared with adult cells. These findings suggest that PKG is developmentally regulated in rabbit heart and is expressed at a much higher level in newborn than in adult cells. The greater expression of PKG in newborn cells could be responsible for differences in the significance of cGMP in adult and newborn rabbit cells.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/biossíntese , Miocárdio/enzimologia , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Northern Blotting , Western Blotting , Canais de Cálcio/metabolismo , DNA Complementar/análise , DNA Complementar/biossíntese , Feminino , Coração/crescimento & desenvolvimento , Técnicas In Vitro , Isoenzimas/biossíntese , Cinética , Masculino , Dados de Sequência Molecular , Miocárdio/citologia , RNA Mensageiro/biossíntese , Coelhos
20.
J Biol Chem ; 274(48): 34301-9, 1999 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-10567406

RESUMO

Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.


Assuntos
Carbazóis , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Alcaloides/farmacologia , Animais , Aorta , Células Cultivadas , GMP Cíclico/análogos & derivados , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/genética , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Indóis/farmacologia , MAP Quinase Quinase 4 , MAP Quinase Quinase Quinases/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tionucleotídeos/farmacologia , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno
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