RESUMO
The systemic response to ischemic stroke is associated with the hepatic acute phase response (APR) that modulates leukocytes recruitment to the injured brain. The inappropriate recruitment of leukocytes to the brain parenchyma can result in blood-brain barrier (BBB) breakdown. Emerging data suggest that peroxisome proliferator-activated receptor beta/delta (PPAR-ß/δ) activation has a potential neuroprotective role in ischemic stroke. However, mechanisms of PPAR-ß/δ mediated protection in ischemic insults remain unclear. In the present study, we determined for the first time, the effects of GW0742, a PPAR-ß/δ agonist on the APR following brain injury and assessed the effects on BBB permeability and tight junction integrity via claudin-5, occludin, and zona occludens-1 expression. C57/BL6 mice were exposed to 1 hour of ischemia and received 10 minutes before reperfusion either a vehicle solution or GW0742. Hepatic expression of chemokines (C-X-C motif ligand: CXCL1, CXCL2, and CXCL10), serum amyloid A-1, tumor necrosis factor alpha, interleukin-1ß, and interleukin-6 was measured, and the extent of brain and hepatic neutrophil infiltration was determined. The results showed that GW0742 treatment decreased infarct volume and edema, reactant production and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. GW0742 significantly reduced BBB leakage and metalloproteinase 9 expression and upregulated the expression of tight junction proteins. These findings may help to guide the experimental and clinical therapeutic use of PPAR-ß/δ agonists against brain injury.
Assuntos
Reação de Fase Aguda/tratamento farmacológico , Barreira Hematoencefálica/patologia , Lesões Encefálicas/tratamento farmacológico , PPAR delta/agonistas , PPAR beta/agonistas , Tiazóis/uso terapêutico , Reação de Fase Aguda/complicações , Reação de Fase Aguda/fisiopatologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/complicações , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Infarto Encefálico/complicações , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Claudinas/genética , Claudinas/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Ocludina/metabolismo , PPAR delta/genética , PPAR delta/metabolismo , PPAR beta/genética , PPAR beta/metabolismo , Permeabilidade/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Apolipoprotein (apo)A-I is the major protein component of HDL and the cofactor for LCAT. We describe a large Spanish kindred, living in the Mediterranean Island of Mallorca, that presents a dominant form of hypoalphalipoproteinemia. The lipid profile of this family was studied because the proband, a 40-year-old male presenting signs of coronary atherosclerosis, showed severe HDL deficiency. However, none of the other family members had a known history of cardiovascular disease. Sequence analysis of the apoA-I gene in affected members identified a 33-base pair deletion, corresponding to residues 165-175 of the mature protein, eliminating the first 11 amino acids of the internal repeat 7. ApoA-I(MALLORCA) is associated with HDL-cholesterol deficiency (concentration ranging from 8-48% of the value in non-carriers), and a 2- to 3-fold decrease in plasma concentrations of apoA-I and apoA-II and endogenous LCAT activity, concomitant with a slight decrease in serum cholesterol efflux capability. Impairment of LCAT activity in HDL particles containing only mutated forms of apoA-I would not explain a pattern of dominant inheritance. HDL particles containing wild type apoA-I and at least one mutant apoA-I may also present impaired LCAT activity and/or other alterations leading to defective HDL maturation, a situation that would increase HDL lipid catabolism. We conclude that amino acids 165-175 of apoA-I are critical for normal HDL metabolism, at least in part because of their role in LCAT activation. However, apoA-I(MALLORCA) is not necessarily associated with clinical signs of atherosclerosis.
