| First Author | Cao Y | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 123 |
| Pages | 1-12 | PubMed ID | 30153439 |
| Mgi Jnum | J:266279 | Mgi Id | MGI:6196152 |
| Doi | 10.1016/j.yjmcc.2018.08.021 | Citation | Cao Y, et al. (2018) Regulatory role of IKKa in myocardial ischemia/reperfusion injury by the determination of M1 versus M2 polarization of macrophages. J Mol Cell Cardiol |
| abstractText | The IkappaB kinase (IKK) complex plays a well-documented role in cancer and immune system. This function has been widely attributed to its role as the master regulator of the NF-kappaB family. Particularly, IKKa, a member of IKK complex, is reported to have various regulating effects in inflammatory and malignant diseases. However, its role as well as its mechanism of function in macrophages following myocardial ischemia and reperfusion (I/R) injury remains unexplored. In vivo, sham or I/R operations were performed on macrophage-specific IKKa knockout (mIKKa(-/-)) mice and their IKKa(flox/flox) littermates. We ligated the left anterior descending (LAD) coronary artery of I/R groups simulating ischemia for 30min, followed by a reperfusion period of 3days and 7days, respectively. The hearts of mIKKa(-/-) mice exhibited significantly increased inflammation and macrophage aggregation as compared to their IKKa(flox/flox) littermates. Moreover, in the mIKKa(-/-) group subjected to I/R macrophages had a tendency to polarize to M1 phenotype. In vitro, we stimulated RAW264.7 cells with Lipopolysaccharides (LPS) after infection by the lentivirus, either knocking-down or overexpressing IKKa. We discovered that a deficiency of IKKa in RAW264.7 caused increased expression of pro-inflammatory markers compared to normal RAW264.7 after LPS stimulation. Inversely, pro-inflammatory factors were inhibited with IKKa overexpression. Mechanistically, IKKa directly combined with RelB to regulate macrophage polarization. Furthermore, IKKa regulated MEK1/2-ERK1/2 and downstream p65 signaling cascades after LPS stimulation. Overall, our data reveals that IKKa is a novel mediator protecting against the development of myocardial I/R injury via negative regulation of macrophage polarization to M1 phenotype. Thus, IKKa may serve as a valuable therapeutic target for the treatment of myocardial I/R injury. |
