Signal Regulatory Protein-α Protects Against Cardiac Hypertrophy Via the Disruption of Toll-Like Receptor 4 Signaling

Abstract

Signal regulatory protein-α (SIRPA/SIRPα) is a transmembrane protein that is expressed in various tissues, including the heart. Previous studies have demonstrated that SIRPA is involved in multiple biological processes, including macrophage multinucleation, skeletal muscle differentiation, neuronal survival, protection against diabetes mellitus, and negative regulation of immune cells. However, the role of SIRPA in cardiac hypertrophy remains unknown. To examine the role of SIRPA in pathological cardiac hypertrophy, we used SIRPA knockout mice and transgenic mice that overexpressed mouse SIRPA in the heart. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We observed downregulation of SIRPA expression in dilated cardiomyopathy human hearts and in animal hearts after aortic banding surgery. Accordingly, SIRPA −/− mice displayed augmented cardiac hypertrophy, which was accompanied by increased cardiac fibrosis and reduced contractile function, as compared with SIRPA +/+ mice 4 weeks after aortic banding. In contrast, transgenic mice with the cardiac-specific SIRPA overexpression exhibited the opposite phenotype in response to pressure overload. Likewise, SIRPA protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we revealed that SIRPA-mediated protection during cardiac hypertrophy involved inhibition of the Toll-like receptor 4/nuclear factor-κB signaling axis. Furthermore, we demonstrated that the disruption of Toll-like receptor 4 rescued the adverse effects of SIRPA deficiency on pressure overload–triggered cardiac remodeling. Thus, our results identify that SIRPA plays a protective role in cardiac hypertrophy through negative regulation of the Toll-like receptor 4/nuclear factor-κB pathway.