Malin C Levin, Pernilla Jirholt, Anna Wramstedt, Maria E Johansson, Anna M Lundberg, Maria Gustafsson Trajkovska, Marcus Ståhlman, Per Fogelstrand, Mikael Brisslert, Linda Fogelstrand, Zhong-Qun Yan, Göran K Hansson, Harry Björkbacka, Sven-Olof Olofsson, Jan Borén
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
Circulation research 2011 Nov 11The 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. We hypothesized that inhibition of Rip2 would protect against development of atherosclerosis. 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. 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.
Malin C Levin, Pernilla Jirholt, Anna Wramstedt, Maria E Johansson, Anna M Lundberg, Maria Gustafsson Trajkovska, Marcus Ståhlman, Per Fogelstrand, Mikael Brisslert, Linda Fogelstrand, Zhong-Qun Yan, Göran K Hansson, Harry Björkbacka, Sven-Olof Olofsson, Jan Borén. Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation. Circulation research. 2011 Nov 11;109(11):1210-8
PMID: 21959219
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