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Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2019
-
Abstract
- Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.
- Subjects :
- 0301 basic medicine
Cardiac fibrosis
vascular endothelial cells
cardiac fibrosis
heart failure
Apoptosis
Constriction, Pathologic
0302 clinical medicine
Enos
Cell Movement
Myocytes, Cardiac
pathological cardiac remodelling
S1PR1
Aorta
Mice, Knockout
biology
Ventricular Remodeling
cardiac hypertrophy
Organ Size
Extracellular Matrix
Up-Regulation
030220 oncology & carcinogenesis
cardiovascular system
Molecular Medicine
Original Article
Signal Transduction
Cardiac function curve
sphingosine 1‐phosphate receptor 1
medicine.medical_specialty
Nitric Oxide Synthase Type III
Cardiomegaly
03 medical and health sciences
Internal medicine
medicine
Human Umbilical Vein Endothelial Cells
Pressure
Animals
Humans
Protein kinase B
Sphingosine-1-Phosphate Receptors
Cell Proliferation
Pressure overload
business.industry
Myocardium
Endothelial Cells
Cell Biology
Original Articles
Fibroblasts
biology.organism_classification
medicine.disease
Angiotensin II
Fibrosis
Capillaries
Rats
030104 developmental biology
Endocrinology
Heart failure
business
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15824934
- Volume :
- 24
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Journal of cellular and molecular medicine
- Accession number :
- edsair.doi.dedup.....348b8f4f935da3110b2e57fea1fe59ee