ACKR3 activation with TC14012 improved aortic valve homeostasis by reducing leaflet thickening, calcium deposition, and lowering peak valve velocity in CXCL12-deficient mice.
Does ACKR3 activation via TC14012 mitigate pathological changes and preserve valvular integrity in a mouse model of calcific aortic valve disease?
Activation of the ACKR3 receptor mitigates maladaptive remodeling and calcification in a mouse model of calcific aortic valve disease, suggesting a potential therapeutic target.
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Abstract Background Calcific aortic valve disease (CAVD), the most prevalent valvular heart disease, remains an irreversible and progressive disorder characterized by fibrocalcific remodeling of the aortic valve. Despite advances in transcatheter aortic valve implantation (TAVI) and surgical interventions, no current treatment effectively attenuates its progression. The chemokine CXCL12, a central regulator of cardiovascular development, emerges as a pivotal yet multifaceted contributor in CAVD pathology. Here, we explore the CXCL12/ACKR3 chemokine axis as a key determinant of valvular homeostasis, unveiling its dual role in both degenerative and reparative pathways. Purpose This study investigates the functional significance of CXCL12 depletion in valvular smooth muscle cells (VSMCs) and its impact on aortic valve remodeling, fibrosis, and calcification. Furthermore, we assess whether activation of ACKR3, an alternative atypical CXCL12 receptor, mitigates pathological changes and preserves valvular integrity. Methods We employed a conditional knockout mice model (SM22α-Cre x CXCL12 flox/flox) to selectively ablate CXCL12 in VSMCs and examined histological, molecular, and functional consequences in aortic valves. Immunofluorescence, histology and western blot analyses were performed to delineate signaling alterations. Additionally, a pharmacological approach utilizing the ACKR3 agonist TC14012 was used to evaluate its therapeutic potential. Echocardiography was performed using high-resolution Doppler ultrasound to measure aortic valve peak velocity, Left ventricular end-diastolic diameter (LVEDD), aortic valve velocity-time integral and Intra ventricular septum diameter systolic and diastolic. Results CXCL12 deletion led to profound ventricular hypertrophy associated with thickening of aortic valve leaflets, enhanced extracellular matrix deposition, and ectopic calcium deposition. Histopathological staining revealed increased proteoglycan accumulation, resembling human AS pathology. Loss of CXCL12 resulted in downregulation of ACKR3, coinciding with activation of AKT and ERK1/2 signaling pathways, known mediators of fibrosis. Notably, ACKR3 activation via TC14012 administration restored aortic valve homeostasis, mitigating valve leaflet thickening, reducing calcium deposition. Echocardiographic analysis demonstrated lower aortic valve velocity-time integral and significantly lowered peak velocity following TC14012 administration demonstrating improved hemodynamic function. Conclusion Our findings establish the CXCL12/ACKR3 axis as a critical regulator of valvular remodeling, bridging, fibrotic, and calcific pathways. Targeting this chemokine axis through ACKR3 activation represents a promising therapeutic avenue for modulating maladaptive remodeling in CAVD.
Jeyakumar et al. (Sat,) reported a other. ACKR3 activation with TC14012 improved aortic valve homeostasis by reducing leaflet thickening, calcium deposition, and lowering peak valve velocity in CXCL12-deficient mice.