RESUMO
Objective- IGF-1 (insulin-like growth factor 1) is a major autocrine/paracrine growth factor, which promotes cell proliferation, migration, and survival. We have shown previously that IGF-1 reduced atherosclerosis and promoted features of stable atherosclerotic plaque in Apoe-/- mice-an animal model of atherosclerosis. The aim of this study was to assess effects of smooth muscle cell (SMC) IGF-1 signaling on the atherosclerotic plaque. Approach and Results- We generated Apoe-/- mice with IGF1R (IGF-1 receptor) deficiency in SMC and fibroblasts (SM22α [smooth muscle protein 22 α]-CreKI/IGF1R-flox mice). IGF1R was decreased in the aorta and adventitia of SM22α-CreKI/IGF1R-flox mice and also in aortic SMC, embryonic, skin, and lung fibroblasts isolated from SM22α-CreKI/IGF1R-flox mice. IGF1R deficiency downregulated collagen mRNA-binding protein LARP6 (La ribonucleoprotein domain family, member 6) and vascular collagen, and mice exhibited growth retardation. The high-fat diet-fed SM22α-CreKI/IGF1R-flox mice had increased atherosclerotic burden and inflammatory responses. α-SMA (α-smooth muscle actin)-positive plaque cells had reduced proliferation and elevated apoptosis. SMC/fibroblast-targeted decline in IGF-1 signaling decreased atherosclerotic plaque SMC, markedly depleted collagen, reduced plaque fibrous cap, and increased plaque necrotic cores. Aortic SMC isolated from SM22α-CreKI/IGF1R-flox mice had decreased cell proliferation, migration, increased sensitivity to apoptosis, and these effects were associated with disruption of IGF-1-induced Akt signaling. Conclusions- IGF-1 signaling in SMC and in fibroblast is a critical determinant of normal vascular wall development and atheroprotection.
Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica , Regiões Promotoras Genéticas , Receptor IGF Tipo 1/deficiência , Actinas/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apoptose , Aterosclerose/genética , Aterosclerose/patologia , Autoantígenos/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Antígeno SS-BRESUMO
Atopic dermatitis (AD) is an intensely pruritic dermatosis that develops most commonly during early infancy and childhood and may follow a chronic, relapsing course into adulthood. As a chronic disease, AD requires treatment over an extended period of time, and is therefore difficult to treat. The main difficulty stems from poor adherence to treatment by patients for reasons such as frustration with medication efficacy, inconvenience, and fear of side effects. Methods that improve adherence include creating therapeutic plans with patient preferences in mind, early follow-up visit, increasing patient education through workshops, and discussing with patients and their caretakers their fears about treatment methods. AD can be exceedingly detrimental to a patient's quality of life. Simple measures to improve adherence may improve patients' treatment outcomes and quality of life.
