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

Abstract

IL-12α 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-12α on cardiac inflammation, hypertrophy, dysfunction, and lung remodeling in IL-12α gene knockout (KO) mice in response to chronic systolic pressure overload produced by transverse aortic constriction (TAC). Our results showed that IL-12α KO significantly ameliorated TAC-induced left ventricular (LV) failure, as evidenced by a smaller decrease of LV ejection fraction. IL-12α 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-12α 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-12α KO displayed significantly attenuated TAC-induced activation of CD4+ T cells and CD8+ T cells in the lung. Furthermore, IL-12α KO showed significantly suppressed accumulation and activation of pulmonary macrophages and dendritic cells. Taken together, these findings indicate that inhibition of IL-12α is effective in attenuating systolic overload-induced cardiac inflammation, heart failure development, promoting transition from LV failure to lung remodeling and right ventricular hypertrophy.

Inhibition of NK1.1 signaling attenuates pressure overload-induced heart failure, and consequent pulmonary inflammation and remodeling

“…The finding that depletion of NK1.1 + cells had no significant effect on TAC-induced LV hypertrophy supports the notion that NK1.1 + cells might exert a relatively mild effect on TACinduced LV inflammation and remodeling. The findings that TAC resulted in increased infiltration and activation of pulmonary residential macrophages, Ly6C + monocyte-derived macrophages, dendritic cells, and T cells are consistent with our previous reports (4,5,43). The reduced RV leukocyte infiltration, fibrosis, and hypertrophy in mice after depletion of NK1.1 + cells are likely a collective outcome of reduced pulmonary remodeling and their direct anti-inflammatory effect on RV tissues.…”

“…In addition, inhibition of inflammation by induction of endogenous regulatory T cells effectively attenuated the transition from LV failure to lung remodeling and RV hypertrophy in mice with existing LV failure ( 5 ). Recently, we further demonstrated that IL12α KO significantly attenuated TAC-induced LV hypertrophy and failure, pulmonary T cell activation, inflammation, fibrosis, and vessel remodeling ( 44 ). Moreover, studies from other groups also demonstrated that LV NK cells, residential macrophages, and monocyte-derived macrophages were significantly increased in mice after TAC ( 31 , 45 ).…”