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Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation.

Levin, Malin C; Jirholt, Pernilla; Wramstedt, Anna; Johansson, Maria E; Lundberg, Anna M; Gustafsson Trajkovska, Maria; Ståhlman, Marcus; Fogelstrand, Per; Brisslert, Mikael and Fogelstrand, Linda, et al. (2011) In Circulation research 109. p.50-1210
Abstract
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... (More)
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. (Less)
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publication status
published
subject
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Circulation research
volume
109
pages
50 - 1210
publisher
American Heart Association
external identifiers
  • WOS:000296872200008
  • PMID:21959219
  • Scopus:81355160558
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.111.246702
language
English
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yes
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e589d9eb-85a2-4e10-8e39-739a66fca23c (old id 2200958)
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http://www.ncbi.nlm.nih.gov/pubmed/21959219?dopt=Abstract
date added to LUP
2011-11-01 16:36:17
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2017-01-01 07:44:47
@article{e589d9eb-85a2-4e10-8e39-739a66fca23c,
  abstract     = {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.},
  author       = {Levin, Malin C and Jirholt, Pernilla and Wramstedt, Anna and Johansson, Maria E and Lundberg, Anna M and Gustafsson Trajkovska, Maria and Ståhlman, Marcus and Fogelstrand, Per and Brisslert, Mikael and Fogelstrand, Linda and Yan, Zhong-Qun and Hansson, Göran K and Björkbacka, Harry and Olofsson, Sven-Olof and Borén, Jan},
  issn         = {1524-4571},
  language     = {eng},
  pages        = {50--1210},
  publisher    = {American Heart Association},
  series       = {Circulation research},
  title        = {Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation.},
  url          = {http://dx.doi.org/10.1161/CIRCRESAHA.111.246702},
  volume       = {109},
  year         = {2011},
}