Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway.
Animals
Apoptosis
/ drug effects
Benzhydryl Compounds
/ toxicity
Blood Pressure
/ drug effects
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/ genetics
Cell Line
Cells, Cultured
Echocardiography
Electrocardiography
Female
Immunohistochemistry
Male
Mice
Microscopy, Confocal
Myocytes, Cardiac
/ drug effects
Necroptosis
/ drug effects
Necrosis
/ chemically induced
Phenols
/ toxicity
RNA, Messenger
/ metabolism
Receptor-Interacting Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
/ drug effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 03 2020
06 03 2020
Historique:
received:
29
05
2019
accepted:
20
02
2020
entrez:
8
3
2020
pubmed:
8
3
2020
medline:
18
11
2020
Statut:
epublish
Résumé
Epidemiological studies link long term exposure to xenoestrogen Bisphenol-A to adverse cardiovascular effects. Our previous results show that BPA induces hypertension by a mechanism involving CamKII activation and increased redox stress caused by eNOS uncoupling. Recently, CamKII sustained activation has been recognized as a central mediator of programmed cell death in cardiovascular diseases, including necroptosis. However, the role of necroptosis in cardiac response to BPA had not yet been explored. Mice exposed to BPA for 16 weeks showed altered heart function, electrical conduction, and increased blood pressure. Besides, a stress test showed ST-segment depression, indicative of cardiac ischemia. The hearts exhibited cardiac hypertrophy and reduced vascularization, interstitial edema, and large hemorrhagic foci accompanied by fibrinogen deposits. BPA initiated a cardiac inflammatory response, up-regulation of M1 macrophage polarization, and increased oxidative stress, coinciding with the increased expression of CamKII and the necroptotic effector RIP3. In addition, cell death was especially evident in coronary endothelial cells within hemorrhagic areas, and Evans blue extravasation indicated a vascular leak in response to Bisphenol-A. Consistent with the in vivo findings, BPA increased the necroptosis/apoptosis ratio, the expression of RIP3, and CamKII activation in endothelial cells. Necrostatin-1, an inhibitor of necroptosis, alleviated BPA induced cardiac dysfunction and prevented the inflammatory and hemorrhagic response in mice. Mechanistically, silencing of RIP3 reversed BPA-induced necroptosis and CamKII activation in endothelial cells, while inhibition of CamKII activation by KN-93 had no effect on RIP3 expression but decreased necroptotic cell death suggesting that BPA induced necroptosis is mediated by a RIP 3/CamKII dependent pathway. Our results reveal a novel pathogenic role of BPA on the coronary circulation. BPA induces endothelial cell necroptosis, promotes the weakening of coronary vascular wall, which caused internal ventricular hemorrhages, delaying the reparative process and ultimately leading to cardiac dysfunction.
Identifiants
pubmed: 32144343
doi: 10.1038/s41598-020-61014-1
pii: 10.1038/s41598-020-61014-1
pmc: PMC7060177
doi:
Substances chimiques
Benzhydryl Compounds
0
Phenols
0
RNA, Messenger
0
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk3 protein, mouse
EC 2.7.11.1
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
bisphenol A
MLT3645I99
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4190Références
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