Adriane Skaletz-Rorowski, PhD Institute for Arteriosclerosis Research Division of Molecular Cardiology University of Muenster Domagkstrasse 3 48149 Muenster, Germany E-mail: skaletz@uni-muenster.de Heike Eschert, PhD Ewa Pawlus, MD Gunter Breithardt, MD PII S0735-1097(00)01079-2 REFERENCES 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 –21. 2. Grandaliano G, Biswas P, Choudhury GG, Abboud HE. Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesan- gial cells. Kidney Int 1993;44:503– 8. 3. Wejde J, Carlberg M, Hjertman M, Larsson O. Isoprenoid regulation of cell growth: identification of mevalonate-labelled compounds in- ducing DNA synthesis in human breast cancer cells depleted of serum and mevalonate. J Cell Physiol 1993;155:539 – 48. 4. Skaletz-Rorowski A, Mu ¨ller JG, Eschert H, Waltenberger J, Breit- hardt 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 – 4. 6. Skaletz-Rorowski A, Schmidt A, Breithardt G, Buddecke E. Heparin- induced overexpression of basic fibroblast growth factor, basic fibro- blast growth factor receptor, and cell-associated proteoheparan sulfate in cultured coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 1996;16:1063–9. 7. Raines EW, Ross R. Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br Heart J 1993;69:S30 –7. 8. Ferns GAA, Stewart-Lee AL, Anggard EE. Arterial response to mechanical injury: balloon catheter de-endothelialization. Atheroscle- rosis 1992;92:89 –104. 9. Klagsbrun M, Edelman ER. Biological and biochemical properties of fibroblast growth factors: implications for the pathogenesis of athero- sclerosis. Arteriosclerosis 1989;9:269 –78. 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 – 43. REPLY Skaletz-Rorowski raises the issue that HMG-CoA reductase inhibitors have several targets in smooth muscle cell (SMC) proliferation that have not been completely identified yet. We agree with Skaletz-Rorowski and associates that further studies should be performed in order to understand the molecular mech- anisms responsible for the antiproliferative effects of HMG-CoA reductase inhibitors, and we have focused the future research of our laboratory on this important issue. However, the aims of our study were to assess the effects of the HMG-CoA reductase inhibitor simvastatin 1) on smooth muscle cell growth in vitro and 2) on neointimal formation after balloon angioplasty or arterial stenting (1). We demonstrated for the first time, in a model of arterial injury, that the HMG-CoA reductase inhibitor simvastatin re- duced the neointimal hyperplasia in vivo and that this effect was abolished using local administration of mevalonate (1). These data might stimulate further studies to evaluate the effects of HMG- CoA reductase inhibitors in a stenting model of larger animals and eventually in humans. A previous study from our laboratory demonstrated that the inhibition of cellular Ras using a transdominant negative Ras gene reduced significantly the neointimal formation after balloon injury (2). It is also well known that the HMG-CoA reductase inhibitors not only reduce plasma cholesterol levels but also competitively inhibit intracellular synthesis of mevalonate, a precursor of non- sterol compounds such as geranyl-geranyl and farnesyl. This effect on the synthesis of farnesyl radicals inhibits the Ras pathway, a key signal transducer that couples the receptors for diverse extracellular signals to different effectors (3). Skaletz-Rorowski pointed out that bFGF plays an important role on SMC proliferation and that HMG-CoA reductase inhib- itors may reduce the expression of this particular growth factor. Growth factors bind specific plasma membrane receptors and activate a complex network of intracellular kinase cascades. However, it should also be pointed out that the activation of different membrane receptors of growth factors (including bFGF, IGF, EGF, VEGF, PDGF, PIGF, etc.) may induce SMC growth and are involved in the neointimal hyperplasia after vascular injury. In this redundant system, it is unlikely that the inhibition of a single growth factor will reduce the rate of clinical restenosis. Therefore, we believe that much interest should be focused on the intracellular common pathways (as the RAS-MAPKK [2] or cAMP-PKA [4]), key signal transducers that couple the receptors for diverse extracellular signals to different effectors. In this regard, the HMG-CoA reductase inhibitors are good clinical candidates to inhibit common pathways of intracellular kinase cascades. Ciro Indolfi, MD, FACC Laboratory of Clinical and Experimental Interventional Cardiology La Magna Graecia University Via Tommaso Campanella, 115 88100-Catanzaro, Italy E-mail: Indolfi@unicz.it Daniele Torella, MD Massimo Chiariello, MD, FACC PII S0735-1097(00)01078-0 REFERENCES 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 –21. 2. Indolfi C, Avvedimento EV, Rapacciuolo A, et al. Inhibition of cellular RAS prevents smooth muscle cell proliferation after vascular injury in vivo. Nat Med 1995;6:541–5. 3. Indolfi C, Chiariello M, Avvedimento EV. Selective gene therapy of proliferative disorders: sense and antisense. Nat Med 1996;6:634 –5. 4. Indolfi C, Avvedimento EV, Di Lorenzo E, et al. Activation of cAMP-PKA signalling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat Med 1997;3:775–9. 338 Letters to the Editor JACC Vol. 37, No. 1, 2001 January 2001:328 –38