X-Message-Number: 29315
Date: Thu, 15 Mar 2007 20:20:37 -0800 (PST)
From: 
Subject: EPCs and IGF1

[A deficiency of Endothelial Progenitor Cells (EPC) is known to be a key
driver of age associated cardiovascular disease. This is beleived to
eventually overwhelm even the combined advantages of low blood
pressure and cholesterol. Age is also associated with a reduction in IGF1,
and a deficiency of IGF1 is known to be associated with an increased risk
of cardiovascular disease even in the young. It's nice to see a direct
connection now being made between low IGF1 and low EPCs. This implies that
it may prove to be unexpectedly easy to block or at least blunt age
associated increases in cardiovascular mortality.]

Circ Res. 2007 Jan 18; [Epub ahead of print]
Age-Dependent Impairment of Endothelial Progenitor Cells is Corrected by
Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1.
Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Galuppo P, Jakob M,
Tsikas D, Anker SD, Poole-Wilson PA, Borlak J, Ertl G, Bauersachs J.
Universitat Wurzburg, Medizinische Klinik I, Wurzburg, Germany; National
Heart and Lung Institute, Imperial College London, Faculty of Medicine,
London, United Kingdom; Medizinische Hochschule Hannover, Institut fur
Klinische Pharmakologie, Hannover, Germany; Fraunhofer Institut fur
Toxikologie und Experimentelle Medizin, Hannover, Germany.
  Aging is associated with an increased risk for atherosclerosis. A
possible cause is low numbers and dysfunction of endothelial progenitor
cells (EPC) which insufficiently repair damaged vascular walls. We
hypothesized that decreased levels of insulin-like growth factor-1
(IGF-1) during age contribute to dysfunctional EPC. We measured the effect
of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC
in mice and human subjects. We compared EPC number and function in
healthy middle-aged male volunteers (57.4+/-1.4 years) before and after a
10 day treatment with recombinant GH (0.4 mg/d) with that of younger and
elderly male subjects (27.5+/-0.9 and 74.1+/-0.9 years). Middle-aged and
elderly subjects had lower circulating CD133(+)/VEGFR-2(+) EPC with
impaired function and increased senescence. GH treatment in middle-aged
subjects elevated IGF-1 levels (126.0+/-7.2 ng/mL versus 241.1+/-13.8
ng/mL; P<0.0001), increased circulating EPC with improved colony forming
and migratory capacity, enhanced incorporation into tube-like structures,
and augmented endothelial nitric oxide synthase expression in EPC
comparable to that of the younger group. EPC senescence was attenuated,
whereas telomerase activity was increased after GH treatment. Treatment
of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and
improved EPC function, whereas a two day GH treatment did not alter IGF-1
or EPC levels. Ex vivo treatment of EPC from elderly individuals with
IGF-1 improved function and attenuated cellular senescence. IGF-1
stimulated EPC differentiation, migratory capacity and the ability to
incorporate into forming vascular networks in vitro via the IGF-1
receptor. IGF-1 increased telomerase activity, endothelial nitric oxide
synthase expression, phosphorylation and activity in EPC in a
phosphoinositide-3-kinase/Akt dependent manner. Small interference
RNA-mediated knockdown of endothelial nitric oxide synthase in EPC
abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1
reverses age-related EPC dysfunction and may be a novel therapeutic
strategy against vascular disorders with impairment of EPC.
PMID: 17234973

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