Increased transforming growth factor-beta1 circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin

Objectives We sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta1 (TGF-beta1) circulating levels and its production in the monocytes of hypercholesterolemic patients. Background Transforming growth factor-beta1 is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients. Methods We evaluated, in a cross-over study design, plasma TGF-beta1 levels and ex vivo TGF-beta1 production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta1messenger ribonucleic acid (mRNA) expression and TGF-beta1 in vitro production. Results Lipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta1 plasma levels (from 1.7 ± 0.5 ng/ml to 3.1 ± 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 ± 0.8 ng/ml to 3.9 ± 1.0 ng/ml, p < 0.001). The increase in TGF-beta1 levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta1 production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 μM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin. Conclusions 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta1 plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta1 expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested.