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(Circulation. 2003;107:e193.)
© 2003 American Heart Association, Inc.

Correspondence

Low Serum Insulin-Like Growth Factor I Is Associated With Increased Risk of Ischemic Heart Disease

Rainer H. Böger, MD

Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, boeger@uke.uni-hamburg.deHospital Hamurg-Eopp

To the Editor:

In a recent interesting paper by Juul et al¹ and an accompanying editorial by Frystyk et al,² an association between low insulin-like growth factor I (IGF-I) serum levels and the incidence of ischemic heart disease was reported. The inverse nature of this relationship was unexpected by these authors, and a number of possible mechanisms were discussed.

However, in addition to these authors’ hypotheses about the molecular mechanisms behind this finding, one mechanism that may contribute to the reported role of IGF-I in coronary heart disease was not mentioned: There is experimental evidence that endothelial cells possess high-affinity binding sites for IGF-I, and that the vasodilator effect of IGF-I is abrogated by the NO synthase inhibitor N^G-monomethyl-l-arginine (L-NMMA).³ These data suggest that IGF-I induces NO-dependent vasodilation. In humans, IGF-I induces endothelium-dependent vasodilation as well, which can also be blocked by co-infusion of L-NMMA.⁴ Furthermore, we found that the increase in serum IGF-I induced by growth hormone supplementation results in elevated urinary excretion of nitrite/nitrate and cyclic GMP, markers of systemic NO production, in adult patients with acquired growth hormone-deficiency⁵ and in patients with cardiomyopathy. In parallel, total peripheral resistance was reduced in both studies, indicating that peripheral vasodilation occurred.

Thus, there is evidence that NO may mediate the cardiovascular effects of IGF-I. Administration of IGF-I has an immediate positive effect on NO formation by endothelial cells. This NO release, given the well-known antiproliferative and antiatherogenic effects of NO, may antagonize many of the proproliferative effects of IGF-I in the cardiovascular system. Reduced endothelial NO elaboration caused by reduced stimulation of endothelial cells by IGF-I may therefore be responsible for many of the detrimental cardiovascular changes associated with low IGF-I levels and may help to explain the inverse relationship between low IGF-I and an increased incidence of coronary heart disease.

References

1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.[Abstract/Free Full Text]
   
2. Frystyk J, Ledet T, Moller N, et al. Cardiovascular disease and insulin-like growth factor 1. Circulation. 2002; 106: 893–895.[Free Full Text]
   
3. Haylor J, Singh I, El Nahas AM. Nitric oxide inhibitor prevents vasodilation by insulin-like growth factor I. Kidney Int. 1991; 39: 333–335.[Medline] [Order article via Infotrieve]
   
4. Fryburg DA. N^G-monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF-1: possible role of nitric oxide in muscle protein synthesis. J Clin Invest. 1996; 97: 1319–1328.[Medline] [Order article via Infotrieve]
   
5. Böger RH, Skamira C, Bode-Böger SM, et al. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency: a double-blind, placebo-controlled study. J Clin Invest. 1996; 98: 2706–2713.[Medline] [Order article via Infotrieve]
   

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Response

Jan Frystyk, MD, PhD; Thomas Ledet, MD, DSc; Niels Møller, MD, DSc; Allan Flyvbjerg, MD, DSc; Hans Ørskov, MD, DSc

Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark

We find Dr Böger’s hypothesis well founded and attractive. Endothelial cells do indeed have insulin-like growth factor I (IGF-I) receptors,¹ and these cells come into direct contact with circulating IGF-I and its binding proteins. This circulating IGF-I system is what was measured in the interesting work by Juul et al.²

References

1. Frystyk J, Ledet T, Møller N, et al. Cardiovascular disease and insulin-like growth factor I. Circulation. 2002; 106: 893–895.[Free Full Text]
   
2. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.[Abstract/Free Full Text]
   

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Böger, R. H. Articles by Ørskov, H. Search for Related Content PubMed PubMed Citation Articles by Böger, R. H. Articles by Ørskov, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Pathophysiology Chronic ischemic heart disease Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors