Inhibition of smooth muscle cell proliferation after balloon injury

Sammanfattning: Smooth muscle cell proliferation is an important part of the arterial response to injury Insulin like growth factor-I (IGF-I) is involved in regulation of cell proliferation and hypopituitarism is associated with decreased vessel wall response to injury. We investigated the role of vascular IGF-I in vessel wall response to injury. Further, restenosis after balloon angioplasty is decreased in patients with high levels of high density lipoproteins (HDL). We studied the effect of recombinant mutant apolipoprotein A I on arterial response to injury. In the rat model of endoluminal arterial balloon injury we have shown that within days after balloon injury the IGF-I mRNA level in the arterial wall increased several-fold, with concurrent increase in protein concentration and receptor down-regulation. The increased expression of IGF-I appeared to be primarily regulated locally as treatment with supraphysiological doses of growth hormone (GH) increased the IGF-I expression in the vessel wall only two-fold. Treatment of rats with the long-acting somatostatin analog octreotide prevented the injury induced upregulation of the IGF-I gene and was associated with dose dependent inhibition of SMC proliferation and neointimal thickening after balloon injury. The inhibitory effect of octreotide appeared to be IGF-I specific and regulated locally in the vessel wall. Octreotide in the doses used did not affect plasma GH, IGF-I and glucagon concentration or liver IGF-I expression. Transcription factor nuclear factor kB (NF-kB) plays a key role in inflammatory response and is also involved in SMC proliferation. Following balloon injury there was a transient two-fold increase in NF-kB nuclear binding. Treatment of rats with the oxygen radicals scavenger aspirin in high doses inhibited NF-kB nuclear binding and expression of NF-kB dependent intracellular adhesion molecule-l gene. These inhibitory effects of aspirin were associated with decreased SMC proliferation and neointimal thickening. Activation of many transcription factors is regulated by multiple phosphorylations. Treatment with octreotide increased the activity of tissue phosphatases and protein dephosphorylation and consequently inhibited NF-kB and fos/jun complex AP-I activation. Co-treatment of rats with okadaic acid, an inhibitor of tissue phosphatases, prevented the inhibitory effects of octreotide on NF-kB and AP-I activation. Rabbits on high-cholesterol chow treated with apolipoprotein mutant A-I Milano (apo A-I M) had less neointimal thickening after arterial balloon injury compared to untreated rabbits. The macrophage infiltration of the arterial wall was decreased in rabbits treated with apo A-I M suggesting that HDL mutant inhibits the accumulation of the proinflammatory cells in the vessel wall after balloon injury. The mechanism of the inhibitory effect did not appear to be related to the increased reverse cholesterol transport with the HDL mutant as the aortic wall cholesterol content was similar in treated and untreated rabbits. ISBN 91-628-2496-1