Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin.
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.
Marino
Franca
F
Department of Clinical Medicine, University of Insubria, Varese, Italy. franca.marino@uninsubria.it
Guasti
Luigina
L
Cosentino
Marco
M
Ferrari
Marco
M
Rasini
Emanuela
E
Maio
Ramona Consuelo
RC
Cimpanelli
Maria Grazia
MG
Cereda
Elena
E
Crespi
Chiara
C
Simoni
Cinzia
C
Restelli
Daniela
D
Venco
Achille
A
Lecchini
Sergio
S
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
D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein