LETTER TO THE EDITOR
Molecular effects of HMG-CoA reductase inhibitors on smooth muscle cell proliferation
Adriane Skaletz-Rorowski, PhDa,
Heike Eschert, PhD,
Ewa Pawlus, MD and
Gunter Breithardt, MD
a Institute for Arteriosclerosis Research, Division of Molecular Cardiology, University of Muenster, Domagkstrasse 3, 48149 Muenster, Germany
skaletz{at}uni-muenster.de
We read with great interest the report by Indolfi et al. (1). The data reported are very interesting because, to the best of our knowledge, this is the first report demonstrating simultaneously that: 1) a hydroxymethylglutaryl Coenzyme A (HMG-CoA) reductase inhibitor blocks smooth muscle cell (SMC) proliferation in vitro; 2) this inhibitor potently reduces neointimal formation induced by vascular injury in vivo; and 3) the in vitro and in vivo effects are completely abolished by mevalonate but not by cholesterol. The investigators linked the antiproliferative effect of the HMG-CoA reductase inhibitor to suppression of Ras farnesylation and the Ras-mediated MAPK (mitogen-activated protein kinase) transduction pathway.
However, we have evidence that the HMG-CoA reductase inhibitors have several targets (not only the Ras farnesylation) in the SMC proliferation, which have not been completely identified yet. This is in agreement with data of Grandaliano et al. (2), who have described that the inhibition of cell proliferation by simvastatin was not reversed by farnesol. Furthermore, Wejde et al. (3) have demonstrated that farnesol failed to promote the growth of compactin (a lovastatin analogue)-blocked cultured breast cancer cells. In addition, our data have shown that despite lovastatin-mediated inhibition of Ras farnesylation, the activation of MAPK is only partially inhibited (4).
Several lines of evidence suggest that the endogenous basic fibroblast growth factor (bFGF), known to be synthesized by vascular SMC (5,6), plays an important role in the stimulation of SMC proliferation that occurs during atherogenesis (7) and in response to vessel wall injury (8). Furthermore, it has been shown that i) bFGF, released from arterial SMC after injury, is a potent mitogen (9) and ii) bFGF- or injury-induced SMC proliferation is significantly inhibited by anti-bFGF antibodies (10). Thus, bFGF expressed by vascular SMC is a strong mitogenic factor stimulating SMC in an autocrine and paracrine manner. However, no studies about the association between the content of the endogenous bFGF and the HMG-CoA reductase inhibitor treatment of SMC were reported.
Thus, we have analyzed the effects of lovastatin on growth factor-induced DNA synthesis in a dose-dependent manner in human coronary SMC in vitro as well as the influence of the HMG-CoA reductase inhibitor on the expression of the endogenous bFGF. Our [3H] thymidine and cell-counting experiments showed that lovastatin caused a reduction of the DNA synthesis and proliferation in human SMC in a dose-dependent manner. Mevalonate (50 µmol/liter) reduced the inhibition produced by lovastatin (5 µmol/liter) by 90%. In contrast, addition of cholesterol did not overcome the inhibition, demonstrating that these effects are not cholesterol-dependent. Furthermore, lovastatin treatment of SMC (in the concentration range that inhibited SMC proliferation) significantly (p < 0.05) reduced the level of the endogenous bFGF to 55% of control cells. The lovastatin-induced effects were reversed by mevalonate but not by cholesterol.
These findings suggest that HMG-CoA reductase inhibitors suppress cell proliferation by downregulation of the expression of the endogenous bFGF. In light of the present findings of Indolfi et al. (1) and our group, it is likely that HMG-CoA reductase inhibitors target several points in the mitogenic pathway of SMC. First, as described by Indolfi et al. (1), HMG-CoA reductase inhibitors block the farnesylation of Ras and the Ras- mediated activation of MAPK. Second, the inhibitors suppress the endogenous expression of the strong mitogen bFGF. Overall, we agree with the investigators that the growth-inhibitory effects of HMG-CoA reductase inhibitors are cholesterol-independent. The underlying mechanisms, however, still remain to be elucidated in further studies.
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References
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1. Indolfi C, Cioppa A, Stabile E, et al. Effects of hydroxymethylglutaryl Coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000;35:214–221[Abstract/Free Full Text]
2. Grandaliano G, Biswas P, Choudhury GG, Abboud HE. Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Kidney Int. 1993;44:503–508[Medline]
3. Wejde J, Carlberg M, Hjertman M, Larsson O. Isoprenoid regulation of cell growth: identification of mevalonate-labelled compounds inducing DNA synthesis in human breast cancer cells depleted of serum and mevalonate. J Cell Physiol. 1993;155:539–548[CrossRef][Medline]
4. Skaletz-Rorowski A, Müller JG, Eschert H, Waltenberger J, Breithardt G. The effect of lovastatin on bFGF-induced MAPK signaling in coronary smooth muscle cells via phosphatase inhibition. Eur Heart J 2000; Suppl. In Press.
5. Schmidt A, Skaletz-Rorowski A, Breithardt G, Buddecke E. Growth status-dependent changes of bFGF compartmentalization and heparin sulfate structure in arterial smooth muscle cells. Eur J Cell Biol. 1995;67:130–134[Medline]
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7. Raines EW, Ross R. Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br Heart J. 1993;69:S30–S37
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9. Klagsbrun M, Edelman ER. Biological and biochemical properties of fibroblast growth factors: implications for the pathogenesis of atherosclerosis. Arteriosclerosis. 1989;9:269–278[Free Full Text]
10. Lindner V, Reidy MA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci USA. 1991;88:3739–3743[Abstract/Free Full Text]
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