RESUMO
BACKGROUND: Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear. METHODS AND RESULTS: Arterial injury was induced in wild-type (wt), leptin-deficient (lep(ob/ob)), and leptin receptor-deficient (lepr(db/db)) mice. Compared with wt mice, lep(ob/ob) and lepr(db/db) mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr(db/db) mice indicated that the vascular protection in lepr(db/db) mice was not attributable to lack of leptin receptor expression on bone marrow-derived elements. To investigate the role of the lepr-mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr(s/s) mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr(s/s) mice was significantly increased compared with lepr(db/db) mice. CONCLUSIONS: The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.
Assuntos
Pressão Sanguínea/fisiologia , Metabolismo Energético/fisiologia , Leptina/fisiologia , Receptores de Superfície Celular/fisiologia , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia , Túnica Íntima/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Artéria Femoral/lesões , Artéria Femoral/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Receptores para Leptina , Túnica Íntima/citologia , Túnica Íntima/fisiologiaRESUMO
E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-ß complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1(+/-)) were intercrossed to produce ESL-1(-/-) mice, however ESL-1(-/-) mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE(-/-)), ESL-1(+/-) mice were generated and fed western diet. Compared to ApoE(-/-), ESL-1(+)(/)(+) mice, atherosclerotic lesions from ApoE(-/-), ESL-1(+/-) contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality.
Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Perda do Embrião/metabolismo , Haploinsuficiência , Macrófagos/metabolismo , Placa Aterosclerótica , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Sialoglicoproteínas/deficiência , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Colágeno/metabolismo , Modelos Animais de Doenças , Perda do Embrião/genética , Genótipo , Idade Gestacional , Heterozigoto , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Sialoglicoproteínas/genéticaRESUMO
AIMS: Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia. METHODS AND RESULTS: Mice were generated with deficiency of apolipoprotein E (ApoE(-/-)) and either wild-type leptin receptor expression (Lepr(+/+), ApoE(-/-)), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Lepr(db/db), ApoE(-/-)), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling (Lepr(s/s), ApoE(-/-)). At 27 weeks of age (including 7 weeks on a Western diet), Lepr(db/db), ApoE(-/-) developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr(+/+), ApoE(-/-) mice. Despite similar obesity and hyperlipidemia to Lepr(db/db), ApoE(-/-) mice, Lepr(s/s), ApoE(-/-) developed less atherosclerosis than Lepr(db/db), ApoE(-/-) mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr(s/s), ApoE(-/-) mice compared to Lepr(db/db), ApoE(-/-) mice. CONCLUSIONS: In a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.