Abstract
The present review will focus on the role of chloride anion in cardiovascular disease, with special emphasis in the development of hypertensive disease and vascular inflammation. It is known that acute and chronic overload of sodium chloride increase blood pressure and have pro-inflammatory and pro-fibrotic effects on different target organs, but it is unknown how chloride may influence these processes. Chloride anion is the predominant anion in the extracellular fluid and its intracellular concentration is dynamically regulated. As the queen of the electrolytes, it is of crucial importance to understand the physiological mechanisms that regulate the cellular handling of this anion including the different transporters and cellular chloride channels, which exert a variety of functions, such as regulation of cellular proliferation, differentiation, migration, apoptosis, intracellular pH and cellular redox state. In this article, we will also review the relationship between dietary, serum and intracellular chloride and how these different sources of chloride in the organism are affected in hypertension and their impact on cardiovascular disease. Additionally, we will discuss the approach of potential strategies that affect chloride handling and its potential effect on cardiovascular system, including pharmacological blockade of chloride channels and non-pharmacological interventions by replacing chloride by another anion.
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Abbreviations
- 9-AC:
-
9-Anthracene- carboxylic acid
- ANG II:
-
Angiotensin II
- BSND:
-
Bartter syndrome with sensorineural deafness (Barttin)
- CaCCs:
-
Calcium-activated chloride channels
- CaMKII:
-
Ca2+/calmodulin-dependent protein kinase II
- CBS:
-
Cystathionine-β-synthase
- CFTR:
-
Cystic fibrosis transmembrane conductance regulator
- Cl− :
-
Chloride
- ClCs:
-
Chloride channel family
- ClC-1:
-
Chloride channel subtype 1
- ClC-2:
-
Chloride channel subtype 2
- ClC-3:
-
Chloride channel subtype 3
- ClC-4:
-
Chloride channel subtype 4
- ClC-5:
-
Chloride channel subtype 5
- ClC-6:
-
Chloride channel subtype 6
- ClC-7:
-
Chloride channel subtype 7
- ClC-Ka:
-
Chloride channel-kidney subtype a
- ClC-Kb:
-
Chloride channel-kidney subtype b
- CLIC:
-
Chloride intracellular channels
- ClVR:
-
Chloride volume-regulated channel
- CPP:
-
P-Chlorophenoxy-propionic acid
- Dahl-R:
-
Dahl salt-resistant rats
- Dahl-S:
-
Dahl salt-sensitive rats
- DCT:
-
Distal convoluted tubule
- DIDS:
-
4,4′-Diisothiocyanostilbene-2,2′-disulfonic acid
- DOCA:
-
Desoxycorticosterone acetate
- DOCP:
-
Desoxycorticosterone pivalate
- dp/dt:
-
Ratio of pressure change in the ventricular cavity during the isovolemic contraction period
- eNOS :
-
Endothelial nitric oxide synthase
- ERK a/b:
-
Extracellular signal-regulated kinases
- GABAAR:
-
Gamma-aminobutyric acid type A receptors
- GDNF:
-
Glial cell line-derived neurotrophic growth factor
- H2O2 :
-
Hydrogen peroxide
- HCTZ:
-
Hydrochlorothiazide
- HOCl:
-
Hypochlorous acid
- IL:
-
Interleukin
- K+ :
-
Potassium
- K3C6H5O7 :
-
Potassium citrate
- KCC2:
-
K+-Cl− cotransporter 2
- KCl:
-
Potassium chloride
- KHCO3 :
-
Potassium bicarbonate
- MCT:
-
Monocarboxylate transporter family
- MPS:
-
Mononuclear phagocyte system
- Na+ :
-
Sodium
- Na3C6H5O7 :
-
Sodium citrate
- NaCl:
-
Sodium chloride
- NaHCO3 :
-
Sodium bicarbonate
- NF-kB:
-
Nuclear transcription factor kappa beta
- NFA:
-
4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid
- NKCC2:
-
Na+/2Cl−/K+ cotransporter
- NO:
-
Nitric oxide
- NOX:
-
NADPH oxidase
- O2 •− :
-
Superoxide anion
- •OH :
-
Hydroxyl radicals
- ONOO− :
-
Peroxynitrite
- PGE2 :
-
Prostaglandin E2
- PI3K:
-
Phosphatidylinositol 3-kinase
- PKC:
-
Protein kinase C
- PP :
-
Serine-threonine protein phosphatases
- RAS :
-
Renin angiotensin system
- RNS :
-
Reactive nitrogen species
- ROMK1 :
-
Rectifying potassium channel
- ROS :
-
Reactive oxygen species
- SHR :
-
Spontaneously hypertensive rats
- SHR-S:
-
Spontaneously hypertensive rats salt sensitive
- SHRSP:
-
Spontaneously hypertensive rats stroke prone
- SM :
-
Smooth muscle
- SNPs :
-
Single nucleotide polymorphisms
- SOD:
-
Superoxide dismutase
- SV/PP :
-
Stroke volume/pulse pressure ratio
- tAL :
-
Thin ascending limb
- TAL:
-
Thick ascending limb
- TgB1-hPDS:
-
Transgenic mice overexpressing the chloride transporter pendrin in intercalated cells
- TMEM16A:
-
Transmembrane protein with unknown function 16
- TNF-α :
-
Tumour necrosis factor alpha
- TONEBP :
-
Tonicity-responsive enhancer-binding protein
- TPR :
-
Total peripheral resistance
- VEGFC:
-
Vascular endothelial growth factor C
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Funding
This work was supported by grants from the ANPCYT (PICT 2018–01105), Universidad de Buenos Aires (UBACYT 20020170100621BA), Sociedad Argentina de Hipertensión Arterial (Stimulus Grant for Research on Hypertension 2018) and Instituto Universitario de Ciencias de la Salud, Fundación Héctor A. Barceló (BA-Med-039–2017).
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Kouyoumdzian, N.M., Kim, G., Rudi, M.J. et al. Clues and new evidences in arterial hypertension: unmasking the role of the chloride anion. Pflugers Arch - Eur J Physiol 474, 155–176 (2022). https://doi.org/10.1007/s00424-021-02649-5
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DOI: https://doi.org/10.1007/s00424-021-02649-5