Cortisol Mediated ET‐1 Production During Stress: Potential Link to Cardiovascular Disease
Authors: Lopez Pablo J. , Reyes-Rivera Arsenio L. , Vega-Torres Julio D. , Figueroa Johnny D. , Inostroza-Nieves Yaritza 
Published: April 2020

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Stress is a major risk factor for CVD. However, little is known about how stress leads to pathological changes over time, contributing to the development and progression of CVD. Enhancing our understanding of the molecular and cellular mechanisms that are affected following the activation of the hypothalamic‐pituitary‐adrenal (HPA) axis may provide mechanistic links connecting stress and CVD risk. Endothelin‐1 (ET‐1) is one of the most potent vasoconstrictors and it is produced by vascular endothelial cells. Recent evidence indicates that its expression is elevated following stress. However, how ET‐1 expression increases following stress is unknown. This study investigated molecular links connecting stress‐responsive hormonal signals to ET‐1 expression in endothelial cells. We found elevated ET‐1 mRNA and protein levels in heart tissue from Lewis rats exposed to mild psychogenic stressor (1.9 fold ± 0.7 relative to unexposed controls, p<0.05, n=12 rats/group). ET‐1 expression and corticosterone levels were significantly correlated in rats exposed to mild psychogenic stress (r = 0.4770, p < 0.0129; n=12). In vitro studies using the human endothelial cell line EA.hy926 revealed that hydrocortisone significantly increased ET‐1protein levels in a dose response manner (1.8 fold ± 0.4 relative to vehicle treatment, p<0.01,n=4). We found that this effect was abolished when cells were pre‐treated with the glucocorticoid receptor (GR) antagonist mifepristone (p<0.0001). Furthermore, FKBP5 gene knockdown experiments demonstrated that FKBP5 is essential for the production of ET‐1 following GR activation. Our data identifies a novel pathway for GR‐mediated ET‐1 induction, which may provide fundamental understanding of the mechanistic links connecting stress and CVD.

Support or Funding Information

This study was partly supported by the NIH (P20MD006988 and 2R25 GM060507), the Loma Linda University School of Medicine Seed Grant, GRASP Funds to JDF and by the Abbvie Research Fellowship 34254.

EA‐hy926 cells exhibited increased (A) FKBP5 and (B) Edn mRNA levels in a hydrocortisone dose‐specific manner. One‐way ANOVA: relative to control: p<0.05, p<0.01, p<0.001, p<0.0001; n=4. (C‐D) We study 10nM and 100nM of hydrocortisone exposure EA‐hy926 cells for 24 hours with and without Mifepristone. This attenuates hydrocortisone effects on FKBP5 (C) and Edn (D) mRNA levels. Two‐way ANOVA: p<0.05, p<0.01, p<0.001, p<0.0001; n=4. (E) Mifepristone reduces ET‐1 protein levels in EA‐hy926 cells.

Figure 1

FKBP5 is required for the induction of endothelin 1 expression by cortisol. (A) FKBP5 mRNA levels were markedly reduced by FKBP5 siRNA treatment. (B) FKBP5 siRNA treatment blunted the induction of Edn by cortisol. (C) FKBP5 siRNA treatment reduced ET‐1 levels even in the presence high hydrocortisone levels. Two‐way ANOVA: p<0.05, p<0.01, p<0.001, p<0.0001; n=4.

Figure 2