Authors: R S Mughal J L Scragg P Lister P Warburton K Riches D J O’Regan S G Ball N A Turner K E Porter
Publish Date: 2010/05/12
Volume: 53, Issue: 8, Pages: 1761-1771
Abstract
Endothelial cells ECs and smooth muscle cells SMCs play key roles in the development of intimal hyperplasia in saphenous vein SV bypass grafts In diabetic patients insulin administration controls hyperglycaemia but cardiovascular complications remain Insulin is synthesised as a propeptide from which Cpeptide is cleaved and released into the circulation with insulin exogenous insulin lacks Cpeptide Here we investigate modulation of human SV neointima formation and SVEC and SVSMC function by insulin and CpeptideEffects of insulin and Cpeptide on neointima formation organ cultures EC and SMC proliferation cell counting EC migration scratch wound SMC migration Boyden chamber and signalling immunoblotting were examined A realtime RT–PCR array identified insulinresponsive genes and results were confirmed by realtime RT–PCR Targeted gene silencing siRNA was used to assess functional relevanceInsulin 100 nmol/l augmented SV neointimal thickening 70 increase 14 days SMC proliferation 55 increase 7 days and migration 150 increase 6 h effects were abrogated by 10 nmol/l Cpeptide Cpeptide did not affect insulininduced Akt or extracellular signalregulated kinase signalling 15 min but array data and gene silencing implicated sterol regulatory element binding transcription factor 1 SREBF1 Insulin 1–100 nmol/l did not modify EC proliferation or migration whereas 10 nmol/l Cpeptide stimulated EC proliferation by 40 5 daysOur data support a causative role for insulin in human SV neointima formation with a novel counterregulatory effect of proinsulin Cpeptide Thus Cpeptide can limit the detrimental effects of insulin on SMC function Cosupplementing insulin therapy with Cpeptide could improve therapy in insulintreated patients
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