Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment

Cardiovascular Diabetology, Dec 2012

Background In diabetes, a variety of pro-inflammatory cellular changes has been found in various cell types, including monocytes which are known to be involved in all the phases of atherogenesis. Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the pro-atherogenic effects of Ang II whereas the type 2 receptor (AT2R) seems associated with atheroprotection. We sought to investigate the potential changes of AT1R-AT2R expression in human monocytes of type 2 diabetic- hypercholesterolemic patients and in hypercholesterolemic subjects, upon clinical treatment with rosuvastatin. Methods The AT1R membrane protein and mRNA AT1R and AT2R expression in monocytes were investigated in 10 type 2 diabetic-hypercholesterolemic patients and in 10 hypercholesterolemic subjects, before and after 3-month rosuvastatin treatment. Moreover, the serum cytokine levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected. Results As expected, rosuvastatin was associated with a change in the lipid profile in the two groups. Both the membrane protein (P = 0.008) and the AT1R mRNA expression (P = 0.038) were significantly reduced during treatment in the absence of AT2R expression change in diabetic-hypercholesterolemic patients whereas no significant difference was observed in hypercholesterolemic subjects. The serum IL-4 levels were increased during treatment whereas no change was observed in IFN-γ in diabetic-hypercholesterolemic patients. No cytokine change was observed in hypercholesterolemic subjects. Conclusions Our study on monocytes of diabetic-hypercholesterolemic patients, showing a reduced AT1R but not AT2R expression during rosuvastatin treatment, suggests that statin therapy may modulate favorably the AT1-AT2 receptor balance in subjects with coexistent type 2 diabetes.

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Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment

Cardiovascular Diabetology Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment Franca Marino 0 Andrea Maria Maresca 0 Marco Cosentino 0 Luana Castiglioni 0 Emanuela Rasini 0 Christian Mongiardi 0 Ramona C Maio 0 Massimiliano Legnaro 0 Laura Schembri 0 Francesco Dentali 0 Anna Maria Grandi 0 Luigina Guasti 0 0 Department of Clinical and Experimental Medicine, University of Insubria , Varese , Italy Background: In diabetes, a variety of pro-inflammatory cellular changes has been found in various cell types, including monocytes which are known to be involved in all the phases of atherogenesis. Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the pro-atherogenic effects of Ang II whereas the type 2 receptor (AT2R) seems associated with atheroprotection. We sought to investigate the potential changes of AT1R-AT2R expression in human monocytes of type 2 diabetic- hypercholesterolemic patients and in hypercholesterolemic subjects, upon clinical treatment with rosuvastatin. Methods: The AT1R membrane protein and mRNA AT1R and AT2R expression in monocytes were investigated in 10 type 2 diabetic-hypercholesterolemic patients and in 10 hypercholesterolemic subjects, before and after 3-month rosuvastatin treatment. Moreover, the serum cytokine levels of interferon- (IFN-) and interleukin-4 (IL-4) were detected. Results: As expected, rosuvastatin was associated with a change in the lipid profile in the two groups. Both the membrane protein (P = 0.008) and the AT1R mRNA expression (P = 0.038) were significantly reduced during treatment in the absence of AT2R expression change in diabetic-hypercholesterolemic patients whereas no significant difference was observed in hypercholesterolemic subjects. The serum IL-4 levels were increased during treatment whereas no change was observed in IFN- in diabetic-hypercholesterolemic patients. No cytokine change was observed in hypercholesterolemic subjects. Conclusions: Our study on monocytes of diabetic-hypercholesterolemic patients, showing a reduced AT1R but not AT2R expression during rosuvastatin treatment, suggests that statin therapy may modulate favorably the AT1-AT2 receptor balance in subjects with coexistent type 2 diabetes. Type 2 Diabetes; Angiotensin II type 1 receptor; Angiotensin II type 2 receptor; Monocytes; Statin - Background Results from clinical trials show that systemic markers of inflammation correlate considerably with future cardiovascular events, both at baseline and during pharmacological treatments [1]. Atherosclerosis as an immuno-inflammatory disease has been associated with a prevalent T-helper (Th) 1 response, being the Interferon- (IFN-) a key cytokine for proinflammatory response amplification; although controversial, data support an antiatherogenic effect of Th2 responses, and Interleukin (IL)-4, the prototypic Th2-related cytokine, is generally considered as an anti-inflammatory cytokine [2]. The renin-angiotensinsystem has been strongly implicated in atherogenesisrelated pro-inflammatory events. Angiotensin II (Ang II) exerts its effects through the binding of two major receptors: the Ang II type-1 receptor (AT1R) which mediates the majority of the pro-atherogenic well-known Ang II actions and type-2 receptor (AT2R) that is considered counteracting the AT1R-mediated effects [3]. Recently a direct role of AT1R activation in leukocyte and macrophages has been identified in the persistence and/or amplification of microinflammation in vessel walls [4,5]. Although little is known at present about the involvement of AT2Rs in atherosclerosis, these receptors appear to participate importantly in vascular biology with improvement in resistance artery remodeling and appear to be cardioprotective [6-8]. The risk of atherosclerotic cardiovascular disease is increased 2- to 3-fold in type 2 diabetes mellitus and a recent meta-analysis in diabetic patients further strengthens the need of a clinical use of statins in this patient population, irrespectively from the baseline lipid characteristics of the patients [9]. Statins may interfere at various levels with the inflammatory processes leading to atherosclerosis and recent evidence, pointing to an interaction between statins and immune function, showed that isoprenoids could regulate T cell proliferation and Th1 differentiation [10,11]. Moreover, the effects of statins seem to influence pathways leading to Ang II-mediated atherosclerosis and we previously demonstrated, in circulating neutrophils of highcardiovascular risk patients, interferences of treatment on both AT1R expression and the cell membrane translocation Rac 1, a guanosine triphosphatebinding protein playing a key role in Ang IIoperated signaling pathways [12]. Among the circulating immune cells, monocytes are the most studied cell subset in relation to atherosclerosis and a key role of these cells in all the phases of atherog (...truncated)


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Franca Marino, Andrea Maria Maresca, Marco Cosentino, Luana Castiglioni, Emanuela Rasini, Christian Mongiardi, Ramona C Maio, Massimiliano Legnaro, Laura Schembri, Francesco Dentali, Anna Maria Grandi, Luigina Guasti. Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment, Cardiovascular Diabetology, 2012, pp. 153, 11, DOI: 10.1186/1475-2840-11-153