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首页> 外文期刊>Journal of Allergy >Increased Expression of RhoA in Epithelium and Smooth Muscle of Obese Mouse Models: Implications for Isoprenoid Control of Airway Smooth Muscle and Fibroblasts
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Increased Expression of RhoA in Epithelium and Smooth Muscle of Obese Mouse Models: Implications for Isoprenoid Control of Airway Smooth Muscle and Fibroblasts

机译：RhoA在肥胖小鼠模型的上皮和平滑肌中的表达增加：对气道平滑肌和成纤维细胞的类异戊二烯控制的意义

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The simultaneous rise in the prevalence of asthma and obesity has prompted epidemiologic studies that establish obesity as a risk factor for asthma. The alterations in cell signaling that explain this link are not well understood and warrant investigation so that therapies that target this asthma phenotype can be developed. We identified a significant increase in expression of the small GTPase RhoA in nasal epithelial cells and tracheal smooth muscle cells from leptin-deficient (ob/ob) mice compared to their wild-type counterparts. Since RhoA function is dependent on isoprenoid modification, we sought to determine the role of isoprenoid-mediated signaling in regulating the viability and proliferation of human airway smooth muscle cells (ASM) and normal human lung fibroblasts (NHLF). Inhibiting isoprenoid signaling with mevastatin significantly decreased the viability of ASM and NHLF. This inhibition was reversed by geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP), suggesting specificity to the Rho GTPases. Conversely, increasing isoprenoid synthesis significantly increased ASM proliferation and RhoA protein expression. RhoA expression is inherently increased in airway tissue from ob/ob mice, and obesity-entrained alterations in this pathway may make it a novel therapeutic target for treating airway disease in the obese population.
机译：哮喘和肥胖症的患病率同时上升，促使流行病学研究确立了肥胖症为哮喘的危险因素。尚不能很好地理解解释这一联系的细胞信号改变，需要进行调查，以便可以开发出针对这种哮喘表型的疗法。我们从瘦素缺陷型（ob / ob）小鼠的鼻上皮细胞和气管平滑肌细胞中发现，与野生型对应物相比，小GTPase RhoA的表达显着增加。由于RhoA功能取决于类异戊二烯修饰，我们试图确定类异戊二烯介导的信号传导在调节人气道平滑肌细胞（ASM）和正常人肺成纤维细胞（NHLF）的活力和增殖中的作用。用美伐他汀抑制类异戊二烯信号转导显着降低了ASM和NHLF的活力。香叶基香叶基焦磷酸酯（GGPP）逆转了这种抑制作用，但焦磷酸法呢基焦磷酸（FPP）却不能逆转，表明对Rho GTPases具有特异性。相反，增加类异戊二烯合成会显着增加ASM增殖和RhoA蛋白表达。 RhoA表达在ob / ob小鼠的气道组织中固有地增加，并且该途径中的肥胖症携带改变可能使其成为治疗肥胖人群中气道疾病的新型治疗靶标。

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