A unique gene expression signature in visceral adipose tissue identifies a high blood pressure group in patients with Cushing's syndrome

Cushings syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension is a frequent feature of Cushings syndrome, promoting hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most of the major cell types strongly affected in their function by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of visceral adipose tissue (VAT) in response to cortisol excess can impact on systemic blood pressure levels in patients with CS. We, therefore, investigated gene expression signatures in VAT from patients with CS collected during curative adrenal surgery identifying significant alterations. During active CS we observed a strong downregulation of gene programs associated with immunity and inflammation in the VAT. In addition, we observed an clustering of the patients based on VAT gene expression profiles into two groups (CSLow and CSHigh) according to blood pressure levels. The two clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system (RAAS). Renin (REN) was the strongest regulated gene compared to control patients and its expression correlated with increased blood pressure observed in our patients while systemic renin plasma levels were suppressed indicative of an abnormal blood pressure and volume status in response to VAT RAAS activation. Here we show for the first time a relevant contribution of the local RAAS system on systemic blood pressure levels in patients with CS. Patients from the CSHigh group had still a significant increased blood pressure levels 6 months into remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.