IL-12α deficiency attenuates pressure overload-induced cardiac inflammation, hypertrophy, dysfunction, and heart failure progression

IL-12 alpha plays an important role in modulating inflammatory response, fibroblast proliferation and angiogenesis through modulating macrophage polarization or T cell function, but its effect on cardiorespiratory fitness is not clear. Here, we studied the effect of IL-12 alpha on cardiac inflammation, hypertrophy, dysfunction, and lung remodeling in IL-12 alpha gene knockout (KO) mice in response to chronic systolic pressure overload produced by transverse aortic constriction (TAC). Our results showed that IL-12 alpha KO significantly ameliorated TAC-induced left ventricular (LV) failure, as evidenced by a smaller decrease of LV ejection fraction. IL-12 alpha KO also exhibited significantly attenuated TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular weight, and the ratios of them in comparison to body weight or tibial length. In addition, IL-12 alpha KO showed significantly attenuated TAC-induced LV leukocyte infiltration, fibrosis, cardiomyocyte hypertrophy, and lung inflammation and remodeling (such as lung fibrosis and vessel muscularization). Moreover, IL-12 alpha KO displayed significantly attenuated TAC-induced activation of CD4(+) T cells and CD8(+) T cells in the lung. Furthermore, IL-12 alpha KO showed significantly suppressed accumulation and activation of pulmonary macrophages and dendritic cells. Taken together, these findings indicate that inhibition of IL-12 alpha is effective in attenuating systolic overload-induced cardiac inflammation, heart failure development, promoting transition from LV failure to lung remodeling and right ventricular hypertrophy.

Automated summary

IL-12 alpha plays a crucial role in modulating inflammatory response, fibroblast proliferation, angiogenesis, and macrophage polarization and T cell function. In this study, IL-12 alpha knockout (KO) mice were used to investigate its effect on cardiac inflammation, hypertrophy, dysfunction, and lung remodeling in response to chronic systolic pressure overload. The results showed that IL-12 alpha KO significantly ameliorated left ventricular (LV) failure, attenuated LV leukocyte infiltration, fibrosis, and cardiomyocyte hypertrophy, as well as lung inflammation and remodeling. IL-12 alpha KO also suppressed the activation and accumulation of CD4(+) T cells, CD8(+) T cells, pulmonary macrophages, and dendritic cells. These findings suggest that inhibition of IL-12 alpha could be effective in attenuating cardiac inflammation, promoting the transition from LV failure to lung remodeling, and preventing right ventricular hypertrophy.