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.

Angiotensin Type 1 Receptor Expression and Interleukin-8 Production in Polymorphonuclear Leukocytes of Patients With Peripheral Arterial Disease

“…3 PMNs of dyslipidemic subjects at high risk for cardiovascular events and free of clinical manifestations of disease show high levels of IL-8 and high production of reactive oxygen species 13,14 and overexpress AT 1 R messenger RNA (mRNA), which is reduced by 30-day treatment with simvastatin. 15 The latter observation is in line with the ability of statins to exert anti-inflammatory and immunomodulating properties, 16 which also include the ability to directly counteract the AT 1 R-dependent proinflammatory effects of Ang II. 15,17,18 Peripheral arterial disease (PAD) is a progressive atherosclerotic condition, affecting 27 million people in North America and Europe.…”

“…15 The latter observation is in line with the ability of statins to exert anti-inflammatory and immunomodulating properties, 16 which also include the ability to directly counteract the AT 1 R-dependent proinflammatory effects of Ang II. 15,17,18 Peripheral arterial disease (PAD) is a progressive atherosclerotic condition, affecting 27 million people in North America and Europe. 19 PAD is characterized by the occurrence of vascular obstruction in various districts and is associated with very high incidence of myocardial ischemia and stroke.…”

“…Supernatant was recovered and PMNs were separated by Ficoll-Paque Plus density gradient centrifugation, as previously described. 15 No platelets or erythrocytes could be detected by either light microscopic examination or flow cytometric analysis; and purity of the preparations, assessed by flow cytometry, was usually 98%-99%, whereas viability was 95%-98% by the trypan blue exclusion test.…”

“…AT 1 R mRNA levels were evaluated as previously described. 15 Threshold cycle values for the AT 1 R gene (Ct 1 ) were calculated, normalized to 18s RNA (housekeeping gene, Ct 2 ), and finally expressed as 2 2DCt 3 10 6 , where DCt = Ct 2 -Ct 1 . …”

Cardiac Hypertrophy During Hypercholesterolemia and Its Amelioration With Rosuvastatin and Amlodipine

“…28,34,35 These effects of statins may contribute to a reduction in cardiomyocyte hypertrophy noted in this study in hypercholesterolemic mice. Statins have also been shown to have direct inhibitory effect on AT1R expression, 36 which may contribute to the observed effects. Further, the cholesterol-independent or ''pleiotropic'' effects of statins, mediated via intracellular signaling molecules such as the Rho GTPases, influence a variety of pathways that affect actin cytoskeleton.…”