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.
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.


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 125I-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.
Li
G
G
Centre for Cardiovascular Research, Toronto Hospital, University of Toronto, Ontario, Canada.
Li
R K
RK
Mickle
D A
DA
Weisel
R D
RD
Merante
F
F
Ball
W T
WT
Christakis
G T
GT
Cusimano
R J
RJ
Williams
W G
WG
D000787:Angina Pectoris / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D017451:Receptors, Somatomedin; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I