Endocrine Abstracts

Background and Aims: Higher cortisol levels are associated with cardiovascular mortality in the elderly resulting from potential angiostatic effects of glucocorticoids (GCs). These features are replicated in patients with endogenous GCs excess (Cushing’s syndrome) as well as with exogenous hypercortisolism due to excessive pharmacological GCs usage. Both groups present the augmented cardiovascular disease event rate. GCs may also adversely influence remodeling after myocardial infarction via inhibition of angiogenesis. Despite new advances in our understanding of GCs pathophysiology over the past decades, the mechanisms that account for glucocorticoid-related control of vessel generation remain a subject of investigation. Recently, it was proposed that microRNAs (miRNAs), the small noncoding RNAs functioning as antisense regulators of gene expression by targeting mRNA, may have a central role in regulating endothelial function through multiple mechanisms. Thus, the purpose of this study was to evaluate the effects of chronic GC excess on the expression of selected angiogenesis-related miRNAs, called Angio-miRs, expressed in nucleated cells circulating in peripheral blood (PBNCs) of patients with endogenous hypercortisolism either due to corticotrophin-dependent or corticotrophin-independent Cushing’s syndrome (CS).

Material and Methods: Cells were isolated from circulating peripheral blood collected from 35 healthy subjects and 31 patients with endogenous hypercortisolism as a source of miRNAs. A self-validated individual quantitative RT-PCR study was then performed to evaluate the expression levels of selected Angio-miRs in isolated cells. Additionally, using Western blot technique, the endothelin-1 (ET-1) expression in plasma of peripheral blood was assessed to detect endothelial dysfunction in vasculature.

Results: The performed analysis of selected Angio-miRs revealed a significantly increased intracellular expression of angiogenesis-related miRNAs in patients with CS, including miRNA-150-5p and miRNA-223-3p transcripts compared with healthy subjects. To the contrary, three other potent angiogenic miRNAs, such as miRNA-17-5p, miRNA-126-3p, and miRNA-126-5p, were significantly down-regulated in patients with endogenous hypercortisolism in comparison to healthy volunteers. Besides, the ET-1 expression levels in CS were higher than in healthy subjects, thus, indirectly confirming endothelial dysfunction developed in the CS cohort.

Conclusion: Cardiovascular events related to hypercortisolism remain a challenging problem in clinical endocrinology. This study has demonstrated that the chronic excess of GCs in endogenous CS might induce significant dysregulation of selected Angio-miRs involved in the biologic activity of endothelial cells in peripheral vasculature. Indeed, dysregulated miRNAs seem to be promising targets for further research, especially to search for potential therapies for several GC-induced cardiovascular complications.

Acknowledgements: This work was supported by grant no UMO-2011/01/B/NZ5/04224.