IL-12β Gene Deficiency Attenuates Pressure Overload-Induced Cardiac Inflammation, Hypertrophy, Heart Failure Development, and Heart Failure Progression

IL-12 is a heterodimeric proinflammatory cytokine composed of IL-12α and IL-12β subunits and is mainly produced by monocytes/macrophages, dendritic cells, and B cells. IL-12β plays an important role in modulating inflammatory responses by activating the proliferation and differentiation of natural killer cells and T cells to produce interferon-gamma and enhance their anti-tumor and anti-microbial activity. However, the role of IL-12β on heart failure (HF) development and HF progression is unknown. Here, we investigated the effect of IL-12β on cardiac inflammation, hypertrophy, dysfunction, and HF progression in response to chronic pressure overload produced by transverse aortic constriction (TAC) by using wild-type (WT) and IL-12β gene knockout (IL-12β KO) mice of both genders. Interestingly, IL-12β KO significantly attenuated chronic pressure overload-induced HF development as evidenced by significantly less reduction in ejection fraction and fractional shortening in both genders. In addition, IL-12β KO also significantly ameliorated the TAC-induced increase of LV weight, LA weight, lung weight, RV weight, and their ratios to body weight or tibial length. Furthermore, IL-12β KO significantly attenuated TAC-induced LV inflammation, cardiomyocyte hypertrophy, fibrosis, and lung inflammation and remodeling. Moreover, RNA sequencing data from the LV tissues of the TAC group showed significant downregulation of genes related to fibrosis and inflammation in IL-12β KO mice compared to WT mice. Taken together, these findings indicate that IL-12β KO effectively attenuates pressure overload-induced cardiac inflammation, hypertrophy, and dysfunction and promotes the transition from LV failure to lung remodeling and RV hypertrophy. This research is funded by NIH grants R01HL161085, R01HL139797, P20GM104357, and P30GM149404. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.