title: Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Corina T
authors.initials: CT
authors.lastname: Madreiter-Sokolowski
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rainer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schauer
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Angelika
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Albert
authors.initials: A
authors.lastname: Woelfler
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Prakash
authors.initials: P
authors.lastname: Doddapattar
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria. Electronic address: dagmar.kratky@medunigraz.at.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001095:Arachidonic Acids / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005989:Glycerides / Q000378:metabolism; D007150:Immunohistochemistry; D008066:Lipolysis; D051379:Mice; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000172:deficiency*; D018377:Neurotransmitter Agents; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018377:Neurotransmitter Agents; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: 2-Arachidonoyl glycerol; Apolipoprotein E-deficient mice; Atherosclerosis; Cannabinoid 2 receptor; Endocannabinoid signaling