The main finding of the present study is the observation that medium-term rosuvastatin clinical treatment is associated with reduced AT1R expression in monocytes of type 2 diabetic patients in the absence of AT2R expression changes.
Various factors act in diabetes to induce atherosclerotic processes and vascular changes. Both hyperinsulinemia and the lipid pattern called atherogenic dyslipidemia are well known pro-atherogenic factors. Recently, the central role of inflammation in diabetes-related atherosclerosis has been underlined by the finding that pro-inflammatory preconditioning is required for the development of high-glucose-induced inflammation in human aortic smooth muscle cells. Moreover, altered cellular functions of various cell types have been related to diabetes and these abnormalities may contribute to systemic inflammation. In particular, in experimental models of diabetes monocytes/macrophages show a decreased phagocytosis and an increased expression of inflammatory mediators, and cells from diabetic subjects exhibit enhanced adherence to the endothelium. As regards the Ang II receptor expression, the functional relevance of up-regulated AT1R expression in diabetes has been underlined by a recent study showing that upregulation of the ligand–Receptor for Advanced Glycation End products pathway via AT1R is an essential mechanism in diabetic atherosclerosis. In diabetic myocardium a significant increase in protein expression and median mRNA expression of the AT1R was reported. In carotid human specimen the mRNA expression of both angiotensinogen and angiotensin-converting enzyme were higher in type 2 diabetic patients than in non-diabetic subjects whereas AT1R mRNA did not differ. Previously we reported that subjects with increased cardiovascular risk according to the Adults Treatment Panel III guidelines had an increased leukocyte AT1R expression at mRNA level and that this expression was reduced during simvastatin treatment but no study has previously focused on cellular changes upon statin treatment in a specific diabetic population[12, 17]. In this study we did not enrolled a control group since the comparison of the receptor expression of high risk subjects has been already investigated. Moreover, we show here for the first time that not only mRNA, but also protein membrane expression of AT1R was significantly reduced during rosuvastatin treatment.
AT2Rs are present in the vasculature and may induce vasorelaxation in vivo[6–8]. Very few studies are at present published on the AT2R expression and functioning in humans, and it is now generally accepted that the AT1R blockade is associated with AT2R overexpression and that AT2R stimulation by Ang II induces counterregulatory vasodilatation that opposes AT1R–mediated vasoconstriction. Indeed, in a study on resistance arteries dissected from gluteal subcutaneous tissues of hypertensive diabetic patients treated with valsartan, Ang II evoked a significant vasodilatory response which was blocked by an AT2R inhibitor. However, studies performed on human internal mammary arteries, AT2R receptor stimulation did not mediate vasodilation and AT2R-mediated vasodilation in the human heart was shown to be limited to coronary microarteries[29, 30].
To our knowledge, no study is available on both AT1R and AT2R modulation by rosuvastatin. In this study, we show for the first time that, after treatment with rosuvastatin, no changes are observed in AT2R mRNA expression in monocytes of type 2 diabetic patients. This finding strengthens the results of reduced AT1R observed during treatment, suggesting a possible favorable modulation of the AT1-AT2 receptor expression during statin treatment. Moreover, according with the already reported finding of a relatively lower AT2R tissue expression in the adult when compared with AT1R expression, we show in human monocytes of diabetic subjects that the AT2R is expressed at a lower level than AT1R. However we have to acknowledge that the results reported here, obtained in a population mainly constituted by male subjects, apply only to type 2 diabetic patients. Even if we have not recruited a control group, the reduction of AT1 receptor expression after rosuvastatin treatment could be explained by a specific effect of diabetes, given that the two groups didn’t differ in their lipid profile. Moreover, the relatively small number of the patients enrolled in this study or the short-term could have influenced the results in hypercholesterolemic patients.
It has been recently reported that rosuvastatin was able to affect the Th1/Th2 response in humans with acute coronary syndrome. In our study, in subjects prone to atherosclerosis but in a stable phase of the process as the type 2 diabetic patients studied, a significant increase of the Th2-profile-related IL-4 was observed whereas we did not evidence a reduction in circulating IFN-γ during treatment. Previously, a reduction in pro-inflammatory cytokine production by circulating monocytes has been associated with statin treatment in humans[32, 33]. As regards statin effects on cytokines directly involved in immunomodulation, although simvastatin-treated dendritic cells showed a Th2 transcription profile which was accompanied by increased Th2 (IL-4, IL-5, and IL-13) and decreased Th1 (IFN-γ) cytokine secretion from the T cells, no longitudinal study in humans has previously shown increased IL-4 levels during clinical statin treatment. Other authors showed no immunomodulatory effect by atorvastatin on the Th1/Th2 balance in human T cells in vitro.