This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Hasdai, D. Articles by Lerman, A. Search for Related Content PubMed PubMed Citation Articles by Hasdai, D. Articles by Lerman, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cholesterol Hazardous Substances DB NITRIC OXIDE Related Collections Structure Pathophysiology Other Vascular biology

(Hypertension. 1999;34:89-95.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Attenuated In Vitro Coronary Arteriolar Vasorelaxation to Insulin-like Growth Factor I in Experimental Hypercholesterolemia

David Hasdai; Michael F. Nielsen; Robert A. Rizza; David R. Holmes, Jr; Darcy M. Richardson; Pinchas Cohen; Amir Lerman

From the Division of Internal Medicine and Cardiovascular Diseases (D.H., D.R.H., D.M.R., A.L.) and the Division of Endocrinology and the Endocrine Research Unit (M.F.N., R.A.R.), Mayo Clinic and Foundation, Rochester, Minn; and the Division of Endocrinology and Department of Pediatrics, University of Pennsylvania, Philadelphia (P.C.).

Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu

Abstract—Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10^-12 to 10^-7 mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10^-4 mol/L N^G-monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10^-2 mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5±1.0 versus 1.9±0.08 mmol/L; P<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80) or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79±6% versus 42±8%; P=0.01) but not insulin (43±6% versus 53±7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.

Key Words: pigs • arteries • insulin • insulin growth factor • hypercholesterolemia

This article has been cited by other articles:

				H. Imrie, A. Abbas, H. Viswambharan, A. Rajwani, R. M. Cubbon, M. Gage, M. Kahn, V. A. Ezzat, E. R. Duncan, P. J. Grant, et al. Vascular Insulin-Like Growth Factor-I Resistance and Diet-Induced Obesity Endocrinology, October 1, 2009; 150(10): 4575 - 4582. [Abstract] [Full Text] [PDF]

				D. K. Bowles, C. L. Heaps, J. R. Turk, K. K. Maddali, and E. M. Price Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation J Appl Physiol, June 1, 2004; 96(6): 2240 - 2248. [Abstract] [Full Text] [PDF]

				M. Ruel, G. F. Wu, T. A. Khan, P. Voisine, C. Bianchi, J. Li, J. Li, R. J. Laham, and F. W. Sellke Inhibition of the Cardiac Angiogenic Response to Surgical FGF-2 Therapy in a Swine Endothelial Dysfunction Model Circulation, September 9, 2003; 108(90101): II-335 - 340. [Abstract] [Full Text] [PDF]

				A. S. Khan, C. D. Lynch, D. C. Sane, M. C. Willingham, and W. E. Sonntag Growth Hormone Increases Regional Coronary Blood Flow and Capillary Density in Aged Rats J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2001; 56(8): B364 - 371. [Abstract] [Full Text] [PDF]

				C. Vecchione, S. Colella, L. Fratta, M. T. Gentile, G. Selvetella, G. Frati, B. Trimarco, and G. Lembo Impaired Insulin-Like Growth Factor I Vasorelaxant Effects in Hypertension Hypertension, June 1, 2001; 37(6): 1480 - 1485. [Abstract] [Full Text] [PDF]

				K. Y. Stokes, E. C. Clanton, J. M. Russell, C. R. Ross, and D. N. Granger NAD(P)H Oxidase-Derived Superoxide Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circ. Res., March 16, 2001; 88(5): 499 - 505. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Porcel, A. Lerman, E. L. Ritman, S. H. Wilson, P. J. M. Best, and L. O. Lerman Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia Circulation, October 24, 2000; 102(17): 2028 - 2030. [Abstract] [Full Text] [PDF]