Role of the vascular endothelial sodium channel activation in the genesis of pathologically increased cardiovascular stiffness.
Aldosterone
/ metabolism
Coronary Circulation
Coronary Vessels
/ metabolism
Endothelial Cells
/ metabolism
Epithelial Sodium Channels
/ metabolism
Female
Fibrosis
Heart Diseases
/ metabolism
Humans
Insulin
/ metabolism
Male
Myocardium
/ metabolism
Receptors, Mineralocorticoid
/ metabolism
Signal Transduction
Sodium
/ metabolism
Vascular Remodeling
Vascular Stiffness
Ventricular Function, Left
Ventricular Remodeling
Aldosterone
Cardiovascular stiffness
Endothelium Na+ channel
Insulin
Mineralocorticoid receptor
Signalling
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
07 01 2022
07 01 2022
Historique:
received:
21
07
2020
revised:
10
09
2020
accepted:
26
10
2020
pubmed:
15
11
2020
medline:
8
3
2022
entrez:
14
11
2020
Statut:
ppublish
Résumé
Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se, this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females.
Identifiants
pubmed: 33188592
pii: 5952671
doi: 10.1093/cvr/cvaa326
pmc: PMC8752352
doi:
Substances chimiques
Epithelial Sodium Channels
0
Insulin
0
Receptors, Mineralocorticoid
0
Aldosterone
4964P6T9RB
Sodium
9NEZ333N27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
130-140Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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