title: Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin.
abstract: Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in the pathogenesis of atherosclerosis (ATH). Ang II promotes a wide array of detrimental processes including a prominent proinflammatory effect, increasingly regarded as a target for therapeutic intervention. Because the proinflammatory effects of Ang II are exerted mainly through the activation of Ang II type 1 receptors (AT1Rs) the present study was devised to investigate by means of real-time polymerase chain reaction (PCR) and flow cytometry techniques the expression of such receptors on circulating polymorphonuclear leukocytes (PMNs) from subjects at high risk for vascular events before and during treatment with simvastatin and in sex- and age-matched healthy controls. In vitro experiments were also performed to assess the ability of simvastatin to interfere with Ang II signaling in human PMNs. In comparison to controls, high-risk subjects had similar AT1R expression on the cell membranes but significantly higher AT1R messenger ribonucleic acid (mRNA) levels. Treatment of high-risk subjects with simvastatin for 30 days resulted in a reduction of AT1R mRNA down to the levels of cells from healthy subjects. In vitro, Ang II-induced activation of the guanosine triphosphate (GTP)-binding protein Rac 1 in human PMNs was inhibited by simvastatin. In conclusion, simvastatin induces downregulation of AT1R expression, interferes with Ang II activity in PMNs, and contributes to the antiinflammatory profile of statins that can explain the therapeutic effects of these drugs.
authors.affiliation: Department of Clinical Medicine, University of Insubria, Varese, Italy. franca.marino@uninsubria.it
authors.forename: Franca
authors.initials: F
authors.lastname: Marino
authors.forename: Luigina
authors.initials: L
authors.lastname: Guasti
authors.forename: Marco
authors.initials: M
authors.lastname: Cosentino
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrari
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rasini
authors.forename: Ramona Consuelo
authors.initials: RC
authors.lastname: Maio
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cimpanelli
authors.forename: Elena
authors.initials: E
authors.lastname: Cereda
authors.forename: Chiara
authors.initials: C
authors.lastname: Crespi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Simoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Restelli
authors.forename: Achille
authors.initials: A
authors.lastname: Venco
authors.forename: Sergio
authors.initials: S
authors.lastname: Lecchini
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology* / Q000517:prevention & control; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007558:Italy; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein