This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Porreca, E. Articles by Cuccurullo, F. Search for Related Content PubMed PubMed Citation Articles by Porreca, E. Articles by Cuccurullo, F.

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

^* 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.

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

This article has been cited by other articles:

				F. Cipollone, M. Fazia, G. Mincione, A. Iezzi, B. Pini, C. Cuccurullo, S. Ucchino, F. Spigonardo, M. Di Nisio, F. Cuccurullo, et al. Increased Expression of Transforming Growth Factor-{beta}1 as a Stabilizing Factor in Human Atherosclerotic Plaques Stroke, October 1, 2004; 35(10): 2253 - 2257. [Abstract] [Full Text] [PDF]

				F. Bea, E. Blessing, B. Bennett, M. Levitz, E. P. Wallace, and M. E. Rosenfeld Simvastatin Promotes Atherosclerotic Plaque Stability in ApoE-Deficient Mice Independently of Lipid Lowering Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1832 - 1837. [Abstract] [Full Text] [PDF]