Elevated Insulin-Like Growth Factor-I and Transforming Growth Factor-beta 1 and Their Receptors in Patients With Idiopathic Hypertrophic Obstructive Cardiomyopathy

A Possible Mechanism

Li, Guangming MD
Li, Ren-Ke MD, PhD
Mickle, Donald A.G. MD
Weisel, Richard D. MD
Merante, Frank PhD
Ball, Warren T. BSc
Christakis, George T. MD
Cusimano, Robert J. MD
Williams, William G. MD

From the Division of Cardiovascular Surgery (R.-K.L., R.D.W., G.T.C., R.J.C., W.G.W.), Department of Clinical Biochemistry (D.A.G.M.), and The Centre for Cardiovascular Research (G.L., F.M., W.T.B.), The Toronto Hospital, General Division, University of Toronto, Toronto, Ontario, Canada.
Guest editor for this article was Dr James T. Willerson, MD, St Luke's Episcopal Hospital/Texas Heart Institute, Houston, Tex.
Correspondence to Dr Ren-Ke Li, Toronto Hospital, General Division, CCRW 1-815, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail [email protected].

Circulation 98(19S):p 144II-149II, November 10, 1998.

Background

Idiopathic hypertrophic obstructive cardiomyopathy (HOCM) is characterized by regional myocardial hypertrophy. In our previous study, we demonstrated that mRNA levels for insulin-like growth factor-I (IGF-I) and transforming growth factor-beta 1 (TGF-beta 1) were elevated in HOCM tissue. In this study, we investigated IGF-I and TGF-beta 1 protein levels and their respective receptor levels and localization.

Methods and Results-Myocardial growth factor protein levels were quantified with the use of chemiluminescent slot blot analysis with monoclonal antibodies against IGF-I and TGF-beta. The growth factor receptor binding sites were evaluated with (¹²⁵) I-labeled IGF-I and TGF-beta 1. The receptors were localized with immunohistochemistry. Data were expressed as mean +/- SEM. IGF-I and TGF-beta protein levels in HOCM myocardium (351.8 +/- 46.5 and 17.4 +/- 2.0 ng/g tissue, respectively; n=6) were significantly higher (P<0.01 for all groups) than in non-HOCM myocardium obtained from patients with aortic stenosis (AS, 182.1 +/- 22.7 and 8.0 +/- 1.2 ng/g tissue, respectively; n=5), stable angina (SA, 117.4 +/- 20.9 and 7.5 +/- 2.7 ng/g tissue, respectively; n=5), and transplanted hearts (TM, 166.3 +/- 30.1 and 6.4 +/- 1.2 ng/g tissue, respectively; n=5). Maximal and high-affinity binding sites for IGF-I receptor in the HOCM were greater (P<0.01 and P<0.05) than the levels in AS, SA, and TM. The maximal receptor binding sites for TGF-beta 1 in HOCM were greater (P<0.05) than those for SA and TM. Immunohistochemistry demonstrated that IGF-I and TGF-beta 1 receptors were located on the cardiomyocytes and TGF-beta 1 receptors were located on the fibroblasts.

Conclusions

Increased IGF-I and TGF-beta 1 gene expression previously observed in HOCM myocardium results in elevated protein levels. IGF-I and TGF-beta 1 signals may be further amplified by increased receptor numbers on cardiomyocytes and fibroblasts. The data suggest a possible autocrine mechanism of IGF-I-stimulated cardiomyocyte hypertrophy and a paracrine mechanism of TGF-beta 1-stimulated extracellular matrix overproduction in HOCM. (Circulation. 1998;98:II-144-II-150.)