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Updated: Oct 10, 2025
Minimally Invasive Transverse Aortic Constriction in Mice
Published on: March 14, 2017
Antagonizing the CX3CR1 Receptor Markedly Reduces Development of Cardiac Hypertrophy After Transverse Aortic
Simona Nemska1,2, Max Gassmann1, Marie-Louise Bang3,4
1Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Insights
The CX3CR1/CX3CL1 pathway is involved in left-ventricular hypertrophy development. Inhibiting CX3CR1 signaling significantly reduced hypertrophy and related gene expression in mice.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Left-ventricular hypertrophy (LVH) is a major risk factor for heart failure and mortality.
- Chemokines and their receptors are implicated in LVH pathogenesis by influencing immune cell recruitment and cardiac remodeling.
Purpose of the Study:
- To investigate the role of chemokine signaling pathways in the development of left-ventricular hypertrophy.
- To identify specific chemokine receptors involved in pressure overload-induced cardiac remodeling.
Main Methods:
- Utilized a mouse model of transverse aortic constriction (TAC) to induce left-ventricular hypertrophy.
- Analyzed messenger RNA (mRNA) expression of various chemokines and chemokine receptors.
- Pharmacologically inhibited CX3CR1 and CCR2 signaling pathways using specific antagonists (AZD8797 and RS504393, respectively).
Main Results:
- Overexpression of multiple chemokine and chemokine receptor mRNAs was observed during LVH progression post-TAC.
- CX3CR1 and CCR2 showed significant upregulation early after TAC.
- Inhibition of CX3CR1 with AZD8797 significantly reduced hypertrophy and expression of hypertrophic (Nppa, Nppb) and profibrotic (Tgfb1, Col1a1) genes.
Conclusions:
- The CX3CR1/CX3CL1 pathway plays a critical role in the pathogenesis of left-ventricular hypertrophy.
- Targeting CX3CR1 signaling represents a potential therapeutic strategy for mitigating LVH.
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.
