CLINICAL STUDY
Increased transforming growth factor-beta1 circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin
Ettore Porreca, MD*,*,
Concetta Di Febbo, MD*,
Giovanna Baccante, PhD*,
Marcello Di Nisio, MD* and
Franco Cuccurullo, MD*
* Department of Medicine and Aging, Atherosclerosis and Thrombosis Section, University of Chieti Medical School, Chieti, Italy
Manuscript received October 22, 2001;
revised manuscript received February 27, 2002,
accepted March 1, 2002.
* Reprint requests and correspondence: Prof. Ettore Porreca, Universita G. D’annunzio, Facolta di Medicina e Chirurgia, Centro Servizi Biomedici (SEBI), Via dei Vestini, 66013, Chieti, Italy.
eporreca{at}unich.it
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-beta1 messenger 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.
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Abbreviations and Acronyms
| | AHA | | American Heart Association | | DNA | | deoxyribonucleic acid | | HDL | | high-density lipoprotein | | HMG-CoA | | 3-hydroxy-3-methyl-glutaryl coenzyme A | | LDL | | low-density lipoprotein | | mRNA | | messenger ribonucleic acid | | TGF-beta1 | | transforming growth factor-beta1 |
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