SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities.

Elena Díaz-García,Ester Zamarrón,Francisco García-Río,Begoña Sánchez-Sánchez,Raquel Casitas,Carolina Cubillos-Zapata,Sara García-Tovar,Ana Jaureguizar,Eduardo López-Collazo

doi:10.3390/jcm9082378

Abstract

Obstructive sleep apnoea (OSA) is associated with several diseases related to metabolic and cardiovascular risk. Although the mechanisms involved in the development of these disorders may vary, OSA patients frequently present an increase in transforming growth factor beta (TGFβ), the activity of which is higher still in patients with hypertension, diabetes or cardiovascular morbidity. Smad4 is a member of the small mother against decapentaplegic homologue (Smad) family of signal transducers and acts as a central mediator of TGFβ signalling pathways. In this study, we evaluate Smad4 protein and mRNA expression from 52 newly diagnosed OSA patients, with an apnoea–hypopnoea index (AHI) ≥30 and 26 healthy volunteers. These analyses reveal that OSA patients exhibit high levels of SMAD4 which correlates with variation in HIF1α, mTOR and circadian genes. Moreover, we associated high concentrations of Smad4 plasma protein with the presence of diabetes, dyslipidaemia and hypertension in these patients. Results suggest that increased levels of SMAD4, mediated by intermittent hypoxaemia and circadian rhythm deregulation, may be associated with cardiometabolic comorbidities in patients with sleep apnoea.

Highlights

Obstructive sleep apnoea (OSA) is a very prevalent disorder which affects around 936 million adults worldwide [1], characterized by recurrent episodes of partial or complete upper airway obstruction associated with intermittent hypoxia and sleep fragmentation
The mechanisms involved in the development of these disorders may vary, OSA patients frequently present an increase in transforming growth factor beta (TGFβ) levels [6], suggesting that the pathways dependent on its activation could play a central role
HIF1α expression induces TGFβ expression, as we have previously reported in OSA patients [6]

Summary

Introduction

Obstructive sleep apnoea (OSA) is a very prevalent disorder which affects around 936 million adults worldwide [1], characterized by recurrent episodes of partial or complete upper airway obstruction associated with intermittent hypoxia and sleep fragmentation. These alterations induce oxidative stress, systemic inflammation, sympathetic activation, and metabolic deregulation [2], and are associated with a high risk of cardiovascular and metabolic disease [3,4,5]. High plasma levels of TGFβ have been reported in patients with hypertension, type 2 diabetes and cardiovascular diseases, suggesting a possible role in their development [8,9]. For example, the pleiotropic effects of TGFβ signalling on metabolism and energy homeostasis are relevant to the aetiology and progression of diabetes [7]

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Results

Conclusion