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SHR Neuro Krebs Kardio Lipid

Vujic, N; Schlager, S; Eichmann, TO; Madreiter-Sokolowski, CT; Goeritzer, M; Rainer, S; Schauer, S; Rosenberger, A; Woelfler, A; Doddapattar, P; Zimmermann, R; Hoefler, G; Lass, A; Graier, WF; Radovic, B; Kratky, D.
Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice.
Atherosclerosis. 2016; 244(6): 9-21. [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Doddapattar Prakash
Göritzer Madeleine
Graier Wolfgang
Hoefler Gerald
Kratky Dagmar
Madreiter-Sokolowski Corina
Radovic Branislav
Rainer Silvia
Rosenberger Angelika
Schauer Silvia
Schlager Stefanie
Vujic Nemanja
Wölfler Albert
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Number of Figures: 8
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Abstract:
Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis. We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation. Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Find related publications in this database (Keywords)
Apolipoprotein E-deficient mice
Atherosclerosis
Cannabinoid 2 receptor
Endocannabinoid signaling
2-Arachidonoyl glycerol
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