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Antagonizing the CX3CR1 Receptor Markedly Reduces Development of Cardiac Hypertrophy After Transverse Aortic Constriction in Mice
- Publication Year :
- 2021
-
Abstract
- Left-ventricular hypertrophy, characterized by cardiomyocyte hypertrophy, interstitial cell proliferation, and immune cell infiltration, is a high risk factor for heart failure and death. Chemokines interacting with G protein-coupled chemokine receptors probably play a role in left-ventricular hypertrophy development by promoting recruitment of activated leukocytes and modulating left-ventricular remodeling. Using the minimally invasive model of transverse aortic constriction in mice, we demonstrated that a variety of chemokine and chemokine receptor messenger Ribonucleic Acid are overexpressed in the early and late phase of hypertrophy progression. Among the chemokine receptors, Cx3cr1 and Ccr2 were most strongly overexpressed and were significantly upregulated at 3, 7, and 14 days after transverse aortic constriction. Ligands of CX3CR1 (Cx3cl1) and CCR2 (Ccl2, Ccl7, Ccl12) were significantly overexpressed in the left ventricle at the early stages after mechanical pressure overload. Pharmacological inhibition of CX3CR1 signaling using the antagonist AZD8797 led to a significant reduction of hypertrophy, whereas inhibition of CCR2 with the RS504393 antagonist did not show any effect. Furthermore, AZD8797 treatment reduced the expression of the hypertrophic marker genes Nppa and Nppb as well as the profibrotic genes Tgfb1 and Col1a1 at 14 days after transverse aortic constriction. These findings strongly suggest the involvement of the CX3CR1/CX3CL1 pathway in the pathogenesis of left-ventricular hypertrophy.
- Subjects :
- Male
medicine.medical_specialty
Time Factors
CX3C Chemokine Receptor 1
Ventricular Function, Left
2705 Cardiology and Cardiovascular Medicine
Transforming Growth Factor beta1
Internal medicine
Natriuretic Peptide, Brain
CX3CR1
medicine
Animals
Myocytes, Cardiac
Receptor
Aorta
Pharmacology
Ventricular Remodeling
Chemokine CX3CL1
business.industry
Aortic constriction
10081 Institute of Veterinary Physiology
Constriction
Fibrosis
Collagen Type I, alpha 1 Chain
Mice, Inbred C57BL
Disease Models, Animal
Thiazoles
Pyrimidines
3004 Pharmacology
Cardiac hypertrophy
10076 Center for Integrative Human Physiology
Cardiology
570 Life sciences
biology
Hypertrophy, Left Ventricular
business
Cardiology and Cardiovascular Medicine
Atrial Natriuretic Factor
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....35756e659c1ce649d7372cff6e0ba085