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

Cushing’s syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension is a frequent feature of Cushing’s 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The study was performed as part of the German Cushing's registry. Patients were diagnosed and underwent adrenalectomy between 2012 and 2021 at the Munich center of the German Cushing's registry. The German Cushing's registry (NeoExNet, No. 152-10) was approved by the LMU ethics committee, and all patients gave written informed consent. ### Funding Statement This work was funded by the Deutsche Forschungsgemeinschaft (DFG) within the collaborative Research Centre 1506 Aging at Interfaces at the Project C05 (Project Number 450627322) to J.T. M.R. received grant support for the German Cushing's Registry CUSTODES by the Else Kröner-Fresenius Stiftung (2012\_A103 and 2015\_A228), by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Projektnummer: 314061271-TRR 205) and by the European Research Council under the European Union Horizon 2020 research and innovation program (grant agreement No. 694913). F.V. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project number: 413635475) and the Munich Clinician Scientist Program (MCSP) of the LMU München. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was performed as part of the German Cushing's registry. Patients were diagnosed and underwent adrenalectomy between 2012 and 2021 at the Munich center of the German Cushing's registry. The German Cushing's registry (NeoExNet, No. 152-10) was approved by the LMU ethics committee, and all patients gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Sequencing data was uploaded to the GEO database and is available under GSE218965. Other data will be available on request or deposited if possible.