Targeting PDE2A of macrophages attenuates sorafenib-induced cardiotoxicity

Methods: A murine model of SIC was established in C57BL/6J mice. Indirect macrophage-cardiomyocyte co-culture systems were used for in vitro mechanistic studies. Macrophages were depleted in vivo using PLX3397. Transcriptomic profiling was performed to identify candidate mediators associated with macrophage-related SIC. PDE2A was further investigated using genetic knockdown and pharmacological inhibition in cellular and animal models. Results: Sorafenib induced cardiac dysfunction, myocardial injury, and inflammatory remodeling in vivo, accompanied by increased cardiac macrophage infiltration and a shift toward a pro-inflammatory phenotype. In vitro, macrophages exacerbated sorafenib-induced cardiomyocyte injury, oxidative stress, and mitochondrial dysfunction, whereas macrophage depletion attenuated SIC in vivo. Transcriptomic analysis identified PDE2A as an upregulated candidate in sorafenib-injured hearts, and this increase was reduced by macrophage depletion. PDE2A expression was preferentially increased in macrophages rather than cardiomyocytes under sorafenib exposure. Genetic or pharmacological inhibition of PDE2A attenuated injury-related phenotypes and inflammatory activation in vitro and alleviated SIC in vivo. Mechanistically, these effects were predominantly associated with cGMP/PKG signaling rather than cAMP/PKA signaling. In tumor-bearing models, BAY60-7550 did not compromise the anti-tumor effect of sorafenib and was associated with enhanced tumor suppression. Conclusion: These findings indicate that sorafenib-induced cardiotoxicity is closely associated with macrophage-driven inflammatory remodeling and identify PDE2A as a candidate mediator of this process. Pharmacological inhibition of PDE2A attenuated cardiac injury while maintaining, and potentially enhancing, the anti-tumor activity of sorafenib, supporting PDE2A as a potential therapeutic target in this setting.