title: Ribosomal protein L13a deficiency in macrophages promotes atherosclerosis by limiting translation control-dependent retardation of inflammation.
abstract: OBJECTIVE
  Unresolved inflammatory response of macrophages plays a pivotal role in the pathogenesis of atherosclerosis. Previously we showed that ribosomal protein L13a-dependent translational silencing suppresses the synthesis of a cohort of inflammatory proteins in monocytes and macrophages. We also found that genetic abrogation of L13a expression in macrophages significantly compromised the resolution of inflammation in a mouse model of lipopolysaccharide-induced endotoxemia. However, its function in the pathogenesis of atherosclerosis is not known. Here, we examine whether L13a in macrophage has a protective role against high-fat diet-induced atherosclerosis.
  
  
  RESULTS
  We bred the macrophage-specific L13a knockout mice L13a Flox(+/+) Cre(+/+) onto apolipoprotein E-deficient background and generated the experimental double knockout mice L13a Flox(+/+) Cre(+/+) apolipoprotein E deficient (apoE(-/-)). L13a Flox(+/+) Cre(-/-) mice on apolipoprotein E-deficient background were used as controls. Control and knockout mice were subjected to high-fat diet for 10 weeks. Evaluation of aortic sinus sections and entire aorta by en face showed significantly higher atherosclerosis in the knockout mice. Severity of atherosclerosis in knockout mice was accompanied by thinning of the smooth muscle cell layer in the media, larger macrophage area in the intimal plaque region and higher plasma levels of inflammatory cytokines. In addition, macrophages isolated from knockout mice had higher polyribosomal abundance of several target mRNAs, thus showing defect in translation control.
  
  
  CONCLUSIONS
  Our data demonstrate that loss of L13a in macrophages increases susceptibility to atherosclerosis in apolipoprotein E-deficient mice, revealing an important role of L13a-dependent translational control as an endogenous protection mechanism against atherosclerosis.
authors.affiliation: From the Department of Biology, Geology, and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH (A.B., D.P., B.M.); Department of Cellular and Molecular Medicine (P.R., J.D.S.), Department of Immunology (W.M.B.), and Department of Molecular Cardiology (M.F), Cleveland Clinic Lerner College of Medicine, Cleveland, OH.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Basu
authors.forename: Darshana
authors.initials: D
authors.lastname: Poddar
authors.forename: Peggy
authors.initials: P
authors.lastname: Robinet
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: Barsanjit
authors.initials: B
authors.lastname: Mazumder
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002634:Chemotaxis, Leukocyte; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D004041:Dietary Fats / Q000633:toxicity; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010537:Peritoneum / Q000473:pathology; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017540:Tunica Media / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D004041:Dietary Fats; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C520792:Rpl13a protein, mouse; D002784:Cholesterol
keywords: atherosclerosis; chemokines; inflammation; macrophages; ribosomal protein L13a, mouse