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FXYD1 Is Protective Against Vascular Dysfunction
FXYD1 Is Protective Against Vascular Dysfunction
- Source :
- Hypertension. 77:2104-2116
- Publication Year :
- 2021
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2021.
-
Abstract
- Nitric oxide (NO) production by eNOS (endothelial NO synthase) is critical for vascular health. Oxidative stress-induced uncoupling of eNOS leads to decreased NO bioavailability, compounded by increased superoxide generation. FXYD1 (FXYD domain containing ion transport regulator 1), a caveolar protein, protects against oxidative inhibition of the Na + -K + -ATPase. We hypothesized that FXYD1 may afford a similar inhibition of oxidative dysregulation of eNOS, providing a broader protection within caveolae. FXYD1-eNOS colocalization was demonstrated by co-immunoprecipitation in heart protein and by proximity ligation assay in human umbilical vein endothelial cells. The functional nature of this partnership was shown by silencing FXYD1 in human umbilical vein endothelial cells, where 50% decreased NO and 2-fold augmented superoxide was shown. Three-dimensional cocultured cardiac spheroids generated from FXYD1 knockout mice were incapable of acetylcholine-induced NO production. Overexpression of FXYD1 in HEK293 cells revealed a possible mechanism, where FXYD1 protected against redox modification of eNOS cysteines. In vivo, vasodilation in response to increasing doses of bradykinin was impaired in knockout mice, and this was rescued in mice by delivery of FXYD1 protein packaged in exosomes. Bloods vessels extracted from knockout mice exhibited increased oxidative and nitrosative stress with evidence of reduce eNOS phosphorylation. Impaired vascular function and augmented superoxide generation were also evident in diabetic knockout mice. Despite this, blood pressure was similar in wildtype and knockout mice, but after chronic angiotensin II infusion, knockout of FXYD1 was associated with a heightened blood pressure response. FXYD1 protects eNOS from dysregulated redox signaling and is protective against both hypertension and diabetic vascular oxidative stress.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Nitric Oxide Synthase Type III
Blood Pressure
030204 cardiovascular system & hematology
Nitric Oxide
medicine.disease_cause
Umbilical vein
Nitric oxide
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Enos
Internal medicine
Human Umbilical Vein Endothelial Cells
Internal Medicine
medicine
Animals
Humans
Mice, Knockout
chemistry.chemical_classification
Reactive oxygen species
biology
Superoxide
Membrane Proteins
Phosphoproteins
biology.organism_classification
Angiotensin II
Coculture Techniques
Oxidative Stress
030104 developmental biology
Endocrinology
chemistry
Knockout mouse
Endothelium, Vascular
Oxidative stress
Subjects
Details
- ISSN :
- 15244563 and 0194911X
- Volume :
- 77
- Database :
- OpenAIRE
- Journal :
- Hypertension
- Accession number :
- edsair.doi.dedup.....65dd58f5a098f53e4d6813db7e27ff52
- Full Text :
- https://doi.org/10.1161/hypertensionaha.120.16884