Macrophage-Specific IκB Kinase α Contributes to Ventricular Remodelling and Dysfunction After Myocardial Infarction

Background: The I kappa B kinase (IKK) complex has been found to have critical functions in cancer and the immune system. In particular, IKK alpha, which is a member of the IKK complex, has been shown to influence the inflammatory response and malignant diseases. However, the role of IKK alpha in macrophages after myocardial infarction (MI) remains largely unknown. Methods: Sham or MI operations were performed on macrophagespecific IKK alpha knockout (mIKK alpha(-/-) mice and IKK alpha(flox/flox) littermates. We ligated the left anterior descending coronary artery of the MI group and observed the results at 3, 7, and 30 days after MI. Results: We discovered more severe cardiac dysfunction with reduced angiogenesis, fibrosis, and collagen deposition in mIKK alpha(-/-) than in IKK alpha(flox/flox). In addition, we also observed that macrophages in mIKK alpha(-/-) were easier to polarize to the M1 phenotype and expressed more proinflammatory factors than IKK alpha(flox/flox). Mechanistically, IKK alpha deficiency in macrophages inhibited the alternative nuclear factor-kappa B/RelB pathway and enhanced the MEK1/2/ERK1/2 pathway. Conclusions: Overall, our data identified IKK alpha in the heart as a novel mediator that protected the heart from a severe inflammatory response and attenuated ventricular remodelling after MI by negatively regulating macrophage polarization to the M1 phenotype. Therefore, IKK alpha may serve as a potential therapeutic target for treatment after MI.