Oral administration of bisphenol A induces high blood pressure through angiotensin II/CaMKII‐dependent uncoupling of eNOS

Abstract

Bisphenol A (BPA) is found in human urine and fat tissue. Higher urinary BPA concentrations are associated with arterial hypertension. To shed light on the underlying mechanism, we orally administered BPA (4 nM to 400 μM in drinking water) to 8-wk-old CD11 mice over 30 d. Mice developed dosage-dependent high blood pressure (systolic 130 ± 12 vs. 170 ± 12 mmHg; EC50 0.4 μM), impairment of acetylcholine (AcH)-induced carotid relaxation (0.66 ± 0.08 vs. 0.44 ± 0.1 mm), a 1.7-fold increase in arterial angiotensin II (AngII), an 8.7-fold increase in eNOS mRNA and protein, and significant eNOS-dependent superoxide and peroxynitrite accumulation. AngII inhibition with 0.5 mg/ml losartan reduced oxidative stress and normalized blood pressure and endothelium-dependent relaxation, which suggests that AngII uncouples eNOS and contributes to the BPA-induced endothelial dysfunction by promoting oxidative and nitrosative stress. Microarray analysis of mouse aortic endothelial cells revealed a 2.5-fold increase in expression of calcium/calmodulin-dependent protein kinase II-α (CaMKII-α) in response to 10 nM BPA, with increased expression of phosphorylated-CaMKII-α in carotid rings of BPA-exposed mice, whereas CaMKII-α inhibition with 100 nM autocamptide-2-related inhibitor peptide (AIP) reduced BPA-mediated increase of superoxide. Administration of CaMKII-α inhibitor KN 93 reduced BPA-induced blood pressure and carotid blood velocity in mice, and reverted BPA-mediated carotid constriction in response to treatment with AcH. Given that CaMKII-α inhibition prevents BPA-mediated high blood pressure, our data suggest that BPA regulates blood pressure by inducing AngII/CaMKII-α uncoupling of eNOS.

Maternal Urinary Bisphenol A Concentration During Midterm Pregnancy and Children’s Blood Pressure at Age 4

“…One recent study reported that feeding BPA to rats for 30 days had increased BP. 36 They also observed an increase of angiotensin II, increased uncoupling of endothelial nitric oxide synthase, and consequent increases in endothelial nitric oxide synthase-dependent superoxide. When they administered angiotensin II inhibitor to these rats, the oxidative stress and BP were reduced, suggesting BPA targets endothelial nitric oxide synthase in a process of angiotensin II-mediated hypertension.…”

“…33 Estudios previos en modelos animales sugirieron que los cambios estructurales o funcionales del aparato cardiovascular, 18,34 la agresión oxidativa 35 y los cambios de metilación del DNA 34 podrían ser causados por la interferencia del BPA en la vía de señales estrogénicas e inducir, con posterioridad, alteración de las funciones cardiovasculares, como la PA. Un estudio reciente comunicó que incorporar BPA en la alimentación de ratas durante 30 días había aumentado la PA. 36 También observaron un aumento de angiotensina II, mayor desacoplamiento de la óxido nítrico sintetasa endotelial y los consiguientes aumentos de superóxido dependiente de óxido nítrico sintetasa endotelial. Cuando administraron un inhibidor de la angiotensina II a estas ratas, se redujo la agresión oxidativa y la PA, lo que sugirió que el BPA tiene como diana a la óxido nítrico sintetasa endotelial en un proceso de hipertensión mediado por angiotensina II.…”

The Choice of Hemodialysis Membrane Affects Bisphenol A Levels in Blood

“…BPA exposure has been linked to inflammation and cardiovascular disease in humans and BPA induces oxidative stress and inflammation in rodents and cultured cells.29,30-33 Oxidative stress was associated with BPA-induced experimental hypertension. 15 BPA induces mitochondrial dysfunction and this has been linked to BPA-associated inflammation. [34][35][36][37] Urinary BPA concentration, a marker of BPA exposure in the general population, is associated with markers of oxidative stress (malondialdehyde and 8-hydroxydeoxyguanosine) and inflammation (white blood cell count and CRP levels) in certain subpopulations such as postmenopausal and pregnant women.…”

“…12 Experimental studies have identified potential mechanisms of BPA nephrotoxicity through injury of glomerular podocytes, oxidative stress, inflammation, and induction of arterial hypertension. [13][14][15] One argument by government agencies for considering safe the use of BPA in the general population is the almost complete and rapid urinary elimination of the conjugated molecule, which decreases the risks of exposure to BPA. 16 Thus, BPA exposure is assessed as urinary BPA concentration in the general population because serum levels are very low when renal function is normal.…”

Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

“…[27][28][29][30] Our findings further document that, although volume-and renin-dependent hypertension similarly increased Cx levels, the abundance of Cx-eNOS complexes differed with the cause of hypertension. Given that angiotensin-II uncouples eNOS and decreases its levels via different signaling pathways, 31,32 it is plausible that these pathways be also differently regulated in renin-and volume-dependent models of hypertension, possibly accounting for the apparent discrepancy mentioned above. The observation that hypertensive 1K1C mice display altered the relaxation of resistance arterioles 16 suggest that the increase in NO resulting from the Cx-eNOS interaction is a compensatory reaction, mitigating the increase in blood pressure induced by volume overload.…”