Endocrine disruptors and arterial hypertension: A developing story.

Endocrine disrupting Chemicals (EDCs) are substances that interfere with hormones by several mechanisms including receptor activation or antagonism, changes in gene and protein expression, modification of signal transduction, and/or epigenetic modifications in hormone-producing cells. A survey conducted by the European Union in a Northern Italian region led to the discovery of a large environmental contamination of drinking water by perfluoroalkyl substances (PFAS). As the exposed population showed a high prevalence of arterial hypertension and cardiovascular disease, we decided to investigate if PFAS could enhance the biosynthesis of aldosterone. To this aim, we exposed human adrenocortical carcinoma HAC15 cells to PFAS and found that PFAS markedly increased aldosterone synthase (CYP11B2) gene expression and aldosterone secretion. Moreover, we found that they promoted reactive oxygen species (ROS) production in mitochondria, the organelles where aldosterone biosynthesis takes place. PFAS also enhanced the effects of the aldosterone secretagogue angiotensin II (Ang II) on CYP11B2 gene expression and aldosterone secretion. We also found that not only PFAS but also polychlorinated biphenyl 126 (PCB126), a chemical compound belonging to a different category of EDCs, can increase CYP11B2 gene expression and aldosterone secretion in adrenocortical cells. This novel information needs to be considered in the context of a widespread exposure to the most common EDC, that is excess Na+ intake, whose detrimental effects on human health occur in the setting of aldosterone production exceeding the physiological needs and lead to high blood pressure, congestion, and cardiovascular and renal damage.

SIRT1, heme oxygenase-1 and NO-mediated vasodilation in a human model of endogenous angiotensin II type 1 receptor antagonism: implications for hypertension.

Reduced NO availability is associated with endothelial dysfunction, hypertension, insulin resistance and cardiovascular remodeling. SIRT1 upregulates eNOS activity and inhibits endothelial cell senescence, and reduced SIRT1 is related to oxidative stress and reduced NO-dependent dilation. Bartter's/Gitelman's syndromes (BS/GS) are rare diseases that feature a picture opposite to that of hypertension in that they present with normo/hypotension, reduced oxidative stress and a lack of cardiovascular remodeling, notwithstanding high levels of angiotensin II and other vasopressors, upregulation of NO system, and increased NO-dependent vasodilation (FMD), as well as increase in both endothelial progenitor cells and insulin sensitivity. To our knowledge, in BS/GS patients SIRT1 has never been evaluated. BS/GS patients' mononuclear cell SIRT1 (western blot), FMD (B-mode scan of the right brachial artery) and heme oxygenase (HO)-1 (sandwich immunoassay), a potent antioxidant protein, were compared with the levels in untreated stage 1 essential hypertensive patients (HPs) and in healthy subjects (C). SIRT1 (1.86 ± 0.29 vs. 1.18 ± 0.18 (HP) vs. 1.45 ± 0.18 (C) densitometric units, P<0.0001) and HO-1 protein (9.44 ± 3.09 vs. 3.70 ± 1.19 (HP) vs. 5.49 ± 1.04 (C) ng ml⁻¹, P<0.0001) levels were higher in BS/GS patients than in the other groups. FMD was also higher in BS/GS patients: 10.52 ± 2.22% vs. 5.99 ± 1 .68% (HP) vs. 7.99 ± 1.13% (C) (ANOVA: P<0.0001). A strong and significant correlation between SIRT1 and FMD was found only in BS/GS patients (r(2)=0.63, P=0.0026). Increased SIRT1 and its direct relationship with increased FMD in BS/GS patients, while strengthening the relationship among SIRT1, NO and vascular function in humans, point toward a role for reduced SIRT1 in the endothelial dysfunction of hypertension.