Rolle der CXCL12 Rezeptoren CXCR4 und CXCR7 in der Atherosklerose und vaskulären Zellhomöostase

• Antragsteller: Professor Dr. Christian Weber
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 29385330

• Erstellungsjahr: 2015

Zusammenfassung der Projektergebnisse

This project has yielded several landmark findings. First of all, the general importance of CXCR4 in protecting against atherosclerosis was demonstrated in a mouse model and this could be related to controlling the homeostasis of neutrophil numbers and function. Next, the differential and cell-specific contributions of CXCR4 on vascular progenitor cells to arterial regeneration could be revealed. Whereas CXCR4 promotes recovery of resident endothelial cells and recruitment of early angiogenic outgrowth cells after arterial injury to limit neointima formation, CXCL12 can drive recruitment of smooth muscle progenitor cells to promote neointima formation as seen in transplant vasculopathy but also the stabilization of primary atherosclerosis. Finally, we have characterized protective effects of the alternative CXCL12 receptor CXCR7 in limiting lesion formation and hyperlipidemia for the first time and have identified a dual complementary pair of endothelial microRNAs for atheroprotection, with miR-126-5p sustaining the proliferative reserve of resident endothelial cells, and miR-126-3p when delivered by apoptotic microparticles inducing auto-regulatory CXCL12 expression to recruit angiogenic cells and thereby promote protective endothelial regeneration. The latter work has been cited about 450-times since 2010, representing a true breakthrough finding.

Projektbezogene Publikationen (Auswahl)

• Adult progenitor cells in vascular remodeling during atherosclerosis. Biol Chem. 2008;389:837-44
  Hristov M, Zernecke A, Schober A, Weber C
  
• Protective role of Cxcr4/Cxcl12 unveils the importance of neutrophils in atherosclerosis. Circ. Res. 2008; 102:209-217
  Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Meiler S, Liehn EA, Schober A, Soehnlein O, Sperandio M, Tacke F, Biessen EA, Weber C
  
• A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Letters 2009; 583:2749-57
  Schwartz V, Lue H, Kraemer S, Krohn R, Ohl K, Korbiel J, Bucala R, Weber C, Bernhagen J
  
• Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Science Signal. 2009; 2:ra81
  Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Köppel T, Nazari Jahantigh M, Lutgens E, Wang S, Olson EN, Schober A, Weber C
  
• Lysophosphatidic acid receptors LPA1 and LPA3 promote CXCL12-mediated smooth muscle progenitor cell recruitment in neointima formation. Circ Res. 2010;107:96-105
  Subramanian P, Karshovska E, Reinhard P, Megens RT, Zhou Z, Akhtar S, Schumann U, Li X, van Zandvoort M, Ludin C, Weber C, Schober A
  
• Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 2010;122:495-506
  Mause SF, Ritzel E, Liehn EA, Hristov M, Bidzhekov K, Mueller-Newen G, Soehnlein O, Weber C
  
• Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 2011; 17:1410-1422
  Weber C, Noels H
  
• CD34+CD140b+ cells and CXCL12 predict the severity of cardiac allograft vasculopathy. Eur. Heart J. 2011;32:476-84
  Schober A, Hristov M, Forbrig R, Kofler S, Löhr B, Schumann U, Krötz F, Leibig M, König A, Kazcmerek I, Reichart B, Klauss V, Weber C, Sohn HY
  
• Double-edged role of the CXCL12-CXCR4 axis in experimental myocardial infarction. J. Am. Coll. Cardiol. 2011; 58:2415-23
  Liehn E, Tuchscheerer N, Kanzler I, Drechsler M, Fraemohs L, Schuh A, Koenen R, Zandler S, Soehnlein O, Hristov M, Grigorescu G, Urs A, Leabu M, Bucur I, Merx M, Zernecke A, Bernhagen J, Schober A, Weber C
  
• Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell. 2013; 153:1025–1035
  Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chèvre R, A-González N, Kunisaki Y, Zhang D, van Rooijen N, Silberstein L, Weber C, Nagasawa T, Frenette PS, Castrillo A, Hidalgo A
  
• Activation of CXCR7 limits atherosclerosis and improves hyperlipidemia by increasing cholesterol uptake in adipose tissue. Circulation 2014;129:1244-53
  Li X, Penfold M, Megens R, Koenen RZ, Thiemann A, Heyll K, Akhtar S, van Zandvoort M, Schall T, Weber C, Schober A
  
• CXCR4 blockade induces atherosclerosis by affecting neutrophil function. J Mol Cell Cardiol. 2014;74:44-52
  Bot I, Daissormont IT, Zernecke A, van Puijvelde GH, Kramp B, de Jager SC, Sluimer JC, Manca M, Hérias V, Westra MM, Bot M, van Santbrink PJ, van Berkel TJ, Su L, Skjelland M, Gullestad L, Kuiper J, Halvorsen B, Aukrust P, Koenen RR, Weber C, Biessen EA
  
• Deficiency of endothelial Cxcr4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in mice. Arterioscler. Thromb. Vasc. Biol. 2014; 34:1209-20
  Noels H, Zhou B, Tilstam PV, Theelen W, Li X, Akhtar S, Simsekyilmaz S, Liehn EA, Schober A, Adams RH, Bernhagen J, Döring Y, Weber C
  
• MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014; 20:368-76
  Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, Megens RT, Heyll K, Noels H, Hristov M, Wang S, Kiessling F, Olson EN, Weber C
  
• The chemokine receptor CXCR4 in cardiovascular disease. Front. Physiol. 2014;5:212
  Döring Y, Pawig L, Weber C, Noels H