RESUMO
Voltage-gated potassium (K(v)) channels play an important role in the regulation of growth factor-induced cell proliferation. We have previously shown that cell cycle activation is induced in oligodendrocytes (OLGs) by complement C5b-9, but the role of K(v) channels in these cells had not been investigated. Differentiated OLGs were found to express K(v)1.4 channels, but little K(v)1.3. Exposure of OLGs to C5b-9 modulated K(v)1.3 functional channels and increased protein expression, whereas C5b6 had no effect. Pretreatment with the recombinant scorpion toxin rOsK-1, a highly selective K(v)1.3 inhibitor, blocked the expression of K(v)1.3 induced by C5b-9. rOsK-1 inhibited Akt phosphorylation and activation by C5b-9 but had no effect on ERK1 activation. These data strongly suggest a role for K(v)1.3 in controlling the Akt activation induced by C5b-9. Since Akt plays a major role in C5b-9-induced cell cycle activation, we also investigated the effect of inhibiting K(v)1.3 channels on DNA synthesis. rOsK-1 significantly inhibited the DNA synthesis induced by C5b-9 in OLG, indicating that K(v)1.3 plays an important role in the C5b-9-induced cell cycle. In addition, C5b-9-mediated myelin basic protein and proteolipid protein mRNA decay was completely abrogated by inhibition of K(v)1.3 expression. In the brains of multiple sclerosis patients, C5b-9 co-localized with NG2(+) OLG progenitor cells that expressed K(v)1.3 channels. Taken together, these data suggest that K(v)1.3 channels play an important role in controlling C5b-9-induced cell cycle activation and OLG dedifferentiation, both in vitro and in vivo.
Assuntos
Ciclo Celular/fisiologia , Desdiferenciação Celular/fisiologia , Complexo de Ataque à Membrana do Sistema Complemento/fisiologia , Canal de Potássio Kv1.3/metabolismo , Esclerose Múltipla/metabolismo , Oligodendroglia/citologia , Animais , Animais Recém-Nascidos , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Esclerose Múltipla/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Venenos de Escorpião/farmacologiaRESUMO
The association of elevated serum uric acid (hyperuricemia, gout) with the presence of classical coronary risk factors and coronary artery disease (CAD) or myocardial infarction (MI) has been analysed in many epidemiological studies. Numerous studies have revealed that hypertension, high body mass index (BMI), lipid disorders (especially raised triglycerides--TG level and low high dense lipoprotein cholesterol HDL-C level), increased creatinine or insulin levels have caused hyperuricemia. No association has been observed between hyperuricemia and diabetes type 2 and uricemia and glicemia. But in some studies the relationship between cholesterol and uric acid levels has been not confirmed. Hyperuricemia has been observed in patients with non-treated hypertension. Gout has often occurred with typical disorders for the metabolic syndrome X. Significant correlation of the serum uric level and the CAD presence and severity of coronary atherosclerosis confirmed by coronary angiography has been observed in women. Hyperuricemia has also indirect influence on progress of CAD by physical activity restriction, what causes sedentary mode of life and lead to obesity. Obesity is a known risk factor diabetes, lipid disorders and hypertension. To recapitulate, it is a matter of controversy as to whether uric acid is an independent cardiovascular risk factor or rather it only represents reinforcement of typical risk factor.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Hiperuricemia/sangue , Hiperuricemia/epidemiologia , Ácido Úrico/sangue , Doenças Cardiovasculares/diagnóstico , Comorbidade , Feminino , Gota/epidemiologia , Humanos , Hiperuricemia/diagnóstico , Obesidade/epidemiologia , Fatores de Risco , Fatores SexuaisRESUMO
OBJECTIVE: Potassium (K(+)) channels on immune cells have gained attention recently as promising targets of therapy for immune-mediated neurological diseases such as multiple sclerosis (MS). We examined K(+) channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course. METHODS: We identified K(+) channels on blood-derived DCs by whole-cell patch-clamp analysis, confirmed by immunofluorescent staining. We also stained K(+) channels in brain sections from MS patients and control subjects. To test functionality, we blocked K(v)1.3 and K(v)1.5 in stimulated DCs with pharmacological blockers or with an inducible dominant-negative K(v)1.x adenovirus construct and analyzed changes in costimulatory molecule upregulation. RESULTS: Electrophysiological analysis of DCs showed an inward-rectifying K(+) current early after stimulation, replaced by a mix of voltage-gated K(v)1.3- and K(v)1.5-like channels at later stages of maturation. K(v)1.3 and K(v)1.5 were also highly expressed on DCs infiltrating MS brain tissue. Of note, we found that CD83, CD80, CD86, CD40, and interleukin-12 upregulation were significantly impaired on K(v)1.3 and K(v)1.5 blockade. INTERPRETATION: These data support a functional role of K(v)1.5 and K(v)1.3 on activated human DCs and further define the mechanisms by which K(+) channel blockade may act to suppress immune-mediated neurological diseases.
Assuntos
Encéfalo/imunologia , Doenças do Sistema Nervoso Central/imunologia , Células Dendríticas/fisiologia , Canal de Potássio Kv1.3/metabolismo , Canal de Potássio Kv1.5/metabolismo , Adenoviridae/genética , Adulto , Idoso , Encéfalo/citologia , Doenças do Sistema Nervoso Central/patologia , Células Dendríticas/efeitos dos fármacos , Feminino , Imunofluorescência , Genes Dominantes , Humanos , Imuno-Histoquímica , Canal de Potássio Kv1.3/antagonistas & inibidores , Canal de Potássio Kv1.3/genética , Canal de Potássio Kv1.5/antagonistas & inibidores , Canal de Potássio Kv1.5/genética , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Mutagênese , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , TransfecçãoRESUMO
The association of elevated serum uric acid (hyperuricemia, gout) with the presence of classical coronary risk factors and coronary artery disease or myocardial infarction has been analysed in many epidemiological studies. In this paper the urid acid metabolism, the factors influancing on this metabolism, the laboratory hyperurycemia criteria and the mode of hyperuricemia treatment are presented. The hyperuricemia and it's collaboration with the other coronary risk factors are analysed as an independent risk factors. Hyperuricemia is described as an increased concentration of uric acid in blood. The urate concentration is elevated when the upper level of arbitrary accepted value is exceeded. That corresponds to the mean value of urate concentration of particular sex and age plus two standard deviations. In most cases of epidemiologic investigations the upper normal range of concentration equals 6 mg/dl for women and 7 mg/dl for men. An increased level of uric acid leads to urate gout (diathesis urica). An increased level of urate in serum is connected with numerous cardiovascular risk factors such as: arterial hypertension, hyperglycemia, diabetes and male sex. But up today, hyperuricemia is not used as independent direct risk factor, so the reduction of uric acid is not obligatory recommended in guidelines for prevention of cardiovascular diseases and stroke.