Overexpression of NF-κB p65 in macrophages ameliorates atherosclerosis in apoE-knockout mice.

The transcription factor NF-κB p65 is a key regulator in the regulation of an inflammatory response and in the pathology of atherosclerosis. However, there is no direct evidence for the role of NF-κB in macrophages in the development of atherosclerosis. We investigated whether macrophage overexpression of p65 in apoE-knockout mice could improve atherosclerosis. Transgenic (Tg) mice overexpressing p65 in macrophages were generated by crossing fatty acid-binding protein 4 (aP2) promoter-controlled p65 mice with apoE-knockout (KO) mice. Tg mice exhibited functional activation of NF-κB signaling in macrophages and fat tissues. We observed that the atherosclerotic lesion was 40% less in the Tg mice compared with the apoE-KO controls fed a standard atherogenic diet for 16 wk (n = 12). The Tg mice were leaner from reduced fat mass by increased energy expenditure. Moreover, the overexpression of p65 in macrophages suppressed foam cell formation. Our results show that there is 1) an increased fatty acid oxidation in macrophages, 2) a reduced scavenger receptor CD36 expression and lipid accumulation in microphages, 3) reduced-inflammation cytokines in serum, and 4) enhanced energy expenditure in Tg mice. Our data suggest that activation of NF-κB in macrophages has atheroprotective effects in mice by enhancing lipid metabolism and energy expenditure.