CCL5 promotes angiotensin II-induced cardiac remodeling through regulation of platelet-driven M2 macrophage polarization.

Rationale: Sustained hypertension induces adverse cardiac remodeling. Platelet activation is instrumental in exacerbating inflammation by engaging with macrophages. C-C chemokine motif ligand 5 (CCL5) is contained within platelet α-granules, and released following platelet activation. This work delineated the specific contributions of CCL5 to platelet function, platelet-induced macrophage polarization, and hypertensive cardiac remodeling.

Methods

CCL5 knockout (KO) mice infused with Angiotensin II (Ang II) were used to identify the role of CCL5 in vivo. CCL5 absence on platelet activation were evaluated on washed platelets. Two distinct models of platelet depletion and reconstitution were utilized to investigate the impact of platelets lacking CCL5. An in vitro co-culture system was established to explore the roles of CCL5-mediated platelet activation in M2 macrophage polarization.

Results

CCL5 KO attenuated the adverse cardiac effects induced by Ang II, including fibrosis, hypertrophy, and functional impairment, accompanied by reduced platelet activation and M2 macrophage polarization in cardiac tissue. Platelet inhibitor administration and platelet depletion/reconstitution experiments revealed that the suppression of platelet activation by CCL5 KO contributed to the amelioration of Ang II-promoted cardiac M2 macrophage polarization and cardiac remodeling. CCL5 KO markedly suppressed the activation of TGF-β1 and NF-κB signaling, an effect observed both in cardiac tissue from Ang II-infused mice and in platelets following ADP stimulation in vitro. In in vitro co-culture systems, rmTGF-β1 reversed CCL5 KO platelet-impaired M2 macrophage polarization. NF-κB inhibition abolished recombinant CCL5 (rmCCL5)-induced platelet activation, while blocking antibodies against CCR1 and CCR3 inhibited rmCCL5-induced NF-κB signaling and platelet activation.

Conclusions

These findings underscore the detrimental role of CCL5-mediated platelet activation in promoting M2 macrophage polarization during hypertensive cardiac remodeling and elucidate the molecular mechanism that CCL5 facilitates platelet-derived TGF-β1 signaling by promoting NF-κB activation via CCR1 and CCR3 receptors. These findings support CCL5 inhibition as a promising strategy against inflammation and cardiac damage.