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 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.
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 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.
Authors: Jo El J Schultz; Sandra A Witt; Betty J Glascock; Michelle L Nieman; Peter J Reiser; Stacey L Nix; Thomas R Kimball; Thomas Doetschman Journal: J Clin Invest Date: 2002-03 Impact factor: 14.808
Authors: Nalini M Rajamannan; Malayannan Subramaniam; Theodore P Abraham; Vlad C Vasile; Michael J Ackerman; David G Monroe; Teng-Leong Chew; Thomas C Spelsberg Journal: J Cell Biochem Date: 2007-02-01 Impact factor: 4.429
Authors: David A Liem; Sanjana Murali; Dibakar Sigdel; Yu Shi; Xuan Wang; Jiaming Shen; Howard Choi; John H Caufield; Wei Wang; Peipei Ping; JiaWei Han Journal: Am J Physiol Heart Circ Physiol Date: 2018-05-18 Impact factor: 4.733