Increased Expression of RhoA in Epithelium and Smooth Muscle of Obese Mouse Models: Implications for Isoprenoid Control of Airway Smooth Muscle and Fibroblasts
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. 1. Introduction The prevalence of both obesity and asthma has increased dramatically in the past two decades [1–3]; over 35% of adults and 17% of children in the USA are categorized as obese [2], and the prevalence of asthma in children under 14 years increased more than 150% between 1980 and 1999 [3]. While numerous epidemiological studies have shown that obesity is associated with the development of asthma [4–8], the alterations in cell signaling induced by obesity that might lead to airway disease are not well understood. Understanding the pathophysiology of airway disease in the growing population of obese asthmatic children is critical to the development of novel therapies specific to this phenotype. Obesity has been shown to influence a number of signaling pathways involved in inflammation and airway hyperresponsiveness [9–14]. Airway responsiveness can be impacted by remodeling of the airways, a process considered to be irreversible. Although the study by Aaron et al. only provides indirect evidence of a relationship between obesity and airway smooth muscle remodeling, it is consistent with the relationship between obesity and vascular remodeling. The increase in airway smooth muscle mass is
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