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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
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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)