Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and NF-ΚB−Mediated Inflammation in Macrophages
Rationale: Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell-type specific causation studies in vivo are lacking, and the molecular mechanisms of potential pro-atherogenic effects remain to be determined.
Objective: To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms.
Methods and Results: We first validated Western-type diet-fed Ldlr-/- mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, correlates with aortic root lesion development. To investigate the importance of macrophage-mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6chi monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the IΚ-kinase-RelA NF-κB pathway.
Conclusions: MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-ΚB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.
- RelA (NF-kB)
- reactive oxygen species
- oxidative stress
- Received July 22, 2013.
- Revision received November 25, 2013.
- Accepted December 2, 2013.