Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation
Rationale: The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-κB (NFκB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.
Objective: We hypothesized that inhibition of Rip2 would protect against development of atherosclerosis.
Methods and Results: Surprisingly, and contrary to our hypothesis, we found that mice transplanted with Rip2−/− bone marrow displayed markedly increased atherosclerotic lesions despite impaired local and systemic inflammation. Moreover, lipid uptake was increased, whereas immune signaling was reduced in Rip2−/− macrophages. Further analysis in Rip2−/− macrophages showed that the lipid accumulation was scavenger-receptor independent and mediated by Toll-like receptor 4 (TLR4)–dependent lipid uptake.
Conclusions: Our data show that lipid accumulation and inflammation are dissociated in the vessel wall in mice with Rip2−/− macrophages. These results for the first time identify Rip2 as a key regulator of cellular lipid metabolism and cardiovascular disease.
- Received April 15, 2011.
- Revision received September 19, 2011.
- Accepted September 20, 2011.
- © 2011 American Heart Association, Inc.