Abstract
Endothelial denudation of rat carotids with a balloon catheter leads to migration and proliferation of medial smooth muscle cells in the neointima. This experimental model of atherosclerosis was used in cholesterol-neutral, normotensive rats to study the effect of Lovastatin as an inhibitor of HMG-CoA(Hydroxymethylglutaryl-Coenzyme A)-reductase by morphometric analysis of arterial cross sections. Treatment with 30 mg/kg bodyweight/day Lovastatin leads to the formation of smaller neointimal thickenings than in the control group. The reduction is about 22%. Accordingly, the vessel lumina were larger — by 42%. This luminal enlargement was not only due to the reduced plaque growth, but also to a reduction in the persistent vessel contraction observed in the control group. This positive effect would indicate that the blood vessels are reacting better towards vessel relaxant factors in the presence of Lovastatin. The reduction in plaque growth, due to inhibition of mevalonate synthesis by Lovastatin, probably involves several intermediate steps, including an inhibition of farnesylation in the cell membrane and of the formation of isopentenyl groups, which result in an inhibition of DNA synthesis and cell proliferation.
Zusammenfassung
Restenosierung von Arterien nach perkutaner transluminaler Angioplastie ist nach wie vor ein Hauptproblem dieser Gefäßerweiterungsmethode. Mehrere Autoren nennen Neuverschlußraten von 16% bis 45%, die innerhalb eines halben Jahres nach chirurgischem Eingriff beobachtet worden sind [11, 12, 15, 16, 18, 22]. Die Ursachen der Restenosierung und des erneuten Gefäßverschlusses nach Ballonangioplastie sind erst wenig verstanden [19]. Plättchenaggregation und Thrombusbildung sowie anhaltende myointimale Proliferation tragen zur Neubildung von Läsionen bei [4, 8, 17]. Die Proliferation und Migration glatter Muskelzellen sowie die Überproduktion von Bindegewebe nach Arterienwandverletzung sind die wesentlichen Merkmale für das gefäßverengende Wachstum von neointimalem Gewebe.
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Literaturverzeichnis
ALBERTS A. Discovery, biochemistry and biology of lovastatin. Am J Cardiol 1988; 62: 10J - 15J.
BECK L, HOSICK TJ, SINENSKY M. Incorporation of a product of mevalonic acid metabolism into proteins of Chinese hamster ovary cell nuclei. J Cell Biol 1988; 107: 1307 1316.
CASEY P, SOLSKI P, DER C, BUSS J. P21 ras is modified by afarnesyl isoprenoid. Proc Natl Acad Sci USA 1989; 86: 8323–8327.
CHESEBRO JH, LAM LYT, BADIMON L, FUSTER V. Restenosis after arterial angioplasty: A hemorrheologic response to injury. Am J Cardiol 1987; 60: 10B - 16B.
CLOWES AW, REIDY MA, CLOWES MM. Mechanisms of stenosis after arterial injury. Lab Invest 1983; 49: 208–215.
CLOWES AW, REIDY MA, CLOWES MM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest 1983; 49: 327333.
FARNSWORTH C, WOLDA S, GELB M, GLOMSET J. Human linin B contains a farnesylated cystein residue. J Biol Chem 1989; 264: 20422–20429.
FAXON DP, SANBORN TA, WEBER VJ, HAUDENSCHILD CC, GOTTSMAN SB, McGAEM WA, RYAN TJ. Restenosis following transluminal angioplasty in experimental atherosclerosis. Arteriosclerosis 1984; 4: 189–195.
GELLMAN J, EZEKOWITZ MD, SAREMBOCK IJ, AZRIN MA, NOCHOMOWITZ LE, LERNER E, HAUDENSCHILD CHC. Effect of lovastatin on intimal hyperplasia after balloon angioplasty: A study in an atherosclerotic hypercholesterolemic rabbit. J Am Coll Cardiol 1991; 17: 251–259.
GOLDSTEIN L, BROWN M. Regulation of the mevalonate pathway. Nature 1990; 343: 425–430.
GRÜNTZIG AR, KING SBI, SCHLUMPF M, SIEGENTHALER W. Long-term follow-up after percutaneous transluminal angioplasty: the early Zürich experience. N Engl J Med 1987; 316: 1127–1132.
GUITERAS VAL P, BOURASSA MG, DAVID PR, BONAN R, CREPEAU J, DYRDA I, LESPERANCE J. Restenosis after successful percutaneous transluminal coronary angioplasty: the Montreal Heart Institute experience. Am J Cardiol 1987; 60: 50B - 55B.
HANCOCK JF, MAGEE Al, CHILDS JE, MARSHALL CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989; 57: 1167–1171.
JACKSON CL, BUSH RC, BOWYER DE. Inhibitory effects of calcium antagonists on balloon catheter-induced arterial smooth muscle cell proliferation and lesion size. Atherosclerosis 1988; 69: 115–122.
KALTENBACH M, KOBER G, SCHERER D, VALLBRACHT C. Recurrence rate after successful coronary angioplasty. Eur Heart J 1985; 6: 276–281.
KUHLMANN U, GREMINGER P, GRÜNTZIG A, SCHNEIDER E, PAULIADIS G, LUESCHER T, STEURER J, SIEGENTHALER W, VETTER W. Long-term experiments in percutaneous transluminal dilation of renal artery stenosis. Am J Med 1985; 79: 692–698.
LAM JYT, CHESEBRO JH, STEELE PM, DEWANJEE MK, BADIMON L, FUSTER V, BYRNE JM, LAMB MB, WENDLAND BI. Deep arterial injury during experimental angioplasty: Relationship to a positive “’indium-labeled platelet scintigram, quantitative platelet deposition, and mural thrombus. J Am Coll Cardiol 1986; 8: 1380–1386.
LEVINE S, EWELS CJ, ROSING D, KENT KM. Coronary angioplasty clinical and angiographic follow-up. Am J Cardiol 1985; 55: 673–676.
ORLANDI C, SINGH J, BELL F, SCHAUB R. Proliferative and lipid metabolism response to balloon angioplasty in canine renal arteries. J Am Coll Cardiol 1990; 15: 1394–1400.
POWELL JS, CLOZEL JP, MÜLLER RKM, KUHN H, HEFT! F, HOSANG M, BAUMGARTNER HR. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245: 186–188.
QUESNEY-HUNEEUSV,WILEYMH,SIPERSTEINMD.Isopentenyladenineasamediator of mevalonate-regulated DNA replication. Proc Natl Acad Sci USA 1980; 77: 5842–5846.
REISFELD D, MASTAS AJ, TELLIS VA, SPRAYRAN S, BAKAL C, SOBERMAN R, GLICKLICH D, VEITH F. Late follow-up of percutaneous transluminal angioplasty for treatment of transplant renal artery stenosis. Transplant Proc 1989; 21: 1955–1956.
SCHAFER W, KIM R, STERNE R, THORNER J, KIM S, RINE J. Genetic and pharmacological suppression of oncogenic mutants in ras genes of yeast and humans. Science 1989; 245: 379–385.
SIEGFRIED M, TAYLOR P, LEFER A. Reversal of cholesterol induced endothelial dysfunction by the HMG-CoA reductase inhibitor lovastatin. Circulation 1990; 82 (Suppl.4): III - 35.
VÖLKER W, FABER V. Aspirin reduces the growth of medial and neointimal thickenings in balloon-injured rat carotid arteries. Stroke 1990; 21: IV.44-IV.45.
WOLDA S, GLOMSET J. Evidence for modification of linin B by a product of mevalonic acid. J Biol Chem 1988; 263: 5997–6000.
WITTE LD, FAIRBANKS KP, BARBU V, GOODMAN DS. Studies on cell proliferation and mevalonic acid metabolism in cultured human fibroblasts. Ann NY Acad Sci 1985; 454: 261–269.
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Völker, W., Faber, V., Brüning, T., Buddecke, E., Eckardt, H. (1992). Inhibition of mevalonate synthesis reduces neointimal outgrowth in balloon injured rat carotid arteries. In: Heinle, H., Schulte, H., Schaefer, H.E. (eds) Arteriosklerotische Gefäßerkrankungen. Vieweg+Teubner Verlag, Wiesbaden. https://doi.org/10.1007/978-3-663-19646-4_38
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DOI: https://doi.org/10.1007/978-3-663-19646-4_38
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