title: Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-gamma ligands Putative contribution of Rho GTPases in statin-induced CD36 expression.
abstract: Scavenger receptor CD36 plays important roles in atherosclerosis, inflammation, thrombosis, and angiogenesis. Statins besides lowering serum cholesterol levels, exhibit a variety of effects on inflammation, coagulation and atherosclerosis lesion stability. PPAR-gamma ligands influence macrophage responses to many inflammatory stimuli. Herein, we investigated in human monocytes the effect of statins alone, and in combination with PPAR-gamma ligands on CD36 expression, as well as the molecular mechanisms underlying the regulatory action of statins. Our results demonstrate that statins upregulate both CD36 surface protein and mRNA by potentiating the transcription of the CD36 gene. Furthermore, the combination of statins and PPAR-gamma ligands has an additive effect on CD36 expression. Effects of statins on CD36 expression were prevented by mevalonate and geranylgeraniol, indicating the requirement of geranylgeranylated proteins for CD36 regulation. Rho GTPases inhibitor C3 exoenzyme reproduced the effect of statins, while Rho activator lysophosphatidic acid downregulated CD36. Transient expression of dominant-negative mutants of RhoA and RhoB induced a significant increased in CD36 promoter activity. Finally, the actin cytoskeleton disrupter cytochalasin D upregulated CD36. These data indicate that Rho proteins are important modulators of CD36 expression, and strongly suggest that statins increased CD36 expression by disrupting cytoskeleton organization by inactivating Rho GTPases. These features prompt to investigate the roles of Rho GTPases and actin cytoskeleton modulators on monocytic functions affected by statins.
authors.affiliation: Servicio de Bioquímica-Investigación, Consejo Superior de Investigaciones Científicas, Hospital Ramón y Cajal, Ctra. Colmenar Viejo km. 9.1, 28034, Madrid, Spain.
authors.forename: Natividad
authors.initials: N
authors.lastname: Ruiz-Velasco
authors.forename: Angeles
authors.initials: A
authors.lastname: Domínguez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Vega
mesh_terms: D000199:Actins / Q000502:physiology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D000924:Anticholesteremic Agents; D018955:CD36 Antigens; D004224:Diterpenes; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D005204:Farnesol; D008148:Lovastatin; C017338:geranylgeraniol; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid