Genetic inhibition of IL-12β suppresses systolic overload-induced cardiac oxidative stress, inflammation, and heart failure development.

Abstract

Inflammation is a key factor in the development of heart failure (HF), with interleukin-12 (IL-12) and interleukin-23 (IL-23) acting as significant pro-inflammatory cytokines, both of which are simultaneously reduced by inhibiting IL-12β. This study utilized IL-12β knockout (KO) mice to investigate whether genetically inhibiting IL-12β could lessen transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as associated lung remodeling. We found that IL-12β KO significantly improved TAC-induced cardiac dysfunction in both male and female mice, evidenced by better left ventricular (LV) ejection fraction and fractional shortening. Additionally, IL-12β KO substantially reduced the TAC-induced increases in the weight of the LV, left atrium, lung, and right ventricle (RV), and their ratios to body weight or tibial length in both sexes. Furthermore, IL-12β KO markedly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and subsequent lung inflammation and remodeling. Bulk LV RNA sequencing demonstrated that IL-12β KO also mitigated TAC-induced changes in LV gene profiles linked to inflammation and fibrosis. We also found that IL-12β KO significantly reduced TAC-induced LV accumulation of various immune cell subsets, activation of CD4and CD8T cells, and the percentage of central memory CD4and CD8T cells within the cardiac drainage lymph nodes. Moreover, IL-12β KO mice exhibited a significant reduction in IFNγCD8and CXCR3CD8T cells in the drainage lymph nodes compared to wild-type mice after TAC. Finally, IL-12β KO and IL-12β blocking antibody significantly decreased TAC-induced LV production of reactive oxygen species (ROS) and the expression of 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE). Collectively, these findings underscore the critical role of IL-12β in systolic overload-induced LV inflammation and HF, likely through mediating cardiac immune cell accumulation, oxidative stress, and fibrosis.