RESUMO
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.
Assuntos
Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Macrófagos/imunologia , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/uso terapêutico , Triazóis/uso terapêutico , Animais , Células Cultivadas , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , PPAR delta/metabolismo , Ligação Proteica , Receptores X de Retinoides/agonistas , Tetra-Hidronaftalenos/farmacologia , Triazóis/farmacologiaRESUMO
The role of K(+) channels in nitric oxide (NO)-induced vasorelaxation has been largely investigated in resistance vessels where iberiotoxin-sensitive MaxiK channels play a predominant role. However, the nature of the K(+) channel(s) involved in the relaxation triggered by NO-releasing compounds [nitroglycerin, NTG; NOR 3 [(+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide]] or atrial natriuretic peptide (ANP) in the conduit vessel aorta has remained elusive. We now demonstrate that, in rat aorta, the relaxation due to these vasorelaxants is not affected by the MaxiK channel blocker iberiotoxin (10(-7)-10(-6) M) as was the control vascular bed used (mesenteric artery). The inability of iberiotoxin to prevent NO/ANP-induced aortic relaxations was not due to lower expression of MaxiK in aorta or due to the predominance of iberiotoxin-resistant channels in this conduit vessel. Aortic relaxations were strongly diminished by 4-aminopyridine (4-AP) (> or =5 x 10(-3) M) or by tetraethylammonium (>2 x 10(-3) M) at concentrations known to inhibit voltage-dependent K(+) (K(v)) 2-type channels but not by other K(+) channel inhibitors, glibenclamide, apamin, charybdotoxin, tertiapin, or E-4031 N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl-]carbonyl]phenyl]methanesulfonamide dihydrochloride). Consistent with a role of K(v)2-type channels, K(v) currents in A7r5 aortic myocytes were stimulated by NTG and inhibited by > or =5 x 10(-3) M 4-AP. Furthermore, immunocytochemistry, immunoblot, and real-time polymerase chain reaction analyses confirmed the presence of K(v)2.1 channels in aorta. K(v)2.1 transcripts were approximately 100-fold more abundant than K(v)2.2. Our results support low-affinity 4-AP-sensitive K(v) channels, assembled at least partially by K(v)2.1 subunit, as downstream effectors of NO/ANP-signaling cascade regulating aortic vasorelaxation and further demonstrate vessel-specific K(+) channel involvement in NO/ANP-induced relaxation.
Assuntos
Aorta Torácica/fisiologia , Fator Natriurético Atrial/fisiologia , Artérias Mesentéricas/fisiologia , Óxido Nítrico/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Vasodilatação/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Fator Natriurético Atrial/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase , Immunoblotting , Técnicas In Vitro , Canais de Potássio Ativados por Cálcio de Condutância Alta/biossíntese , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Guanilil Ciclase Solúvel , Vasodilatação/efeitos dos fármacosRESUMO
A 28-year-old man developed severe infundibular pulmonary stenosis (PS), coronary artery stenosis with sustained ventricular tachycardia (VT) 24 years after mediastinal irradiation (total amount of 40 Gray) for non-Hodgkin's lymphoma. Repair of right ventricular outflow tract and coronary artery bypass graft procedure were performed. Infundibular PS was successfully relieved after operation and VT was also controlled by medication. Mediastinal irradiation often causes various cardiac complications after a latent period. Therefore, continuous careful observation is mandatory in patients with the history of mediastinal irradiation.