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Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC¹ Division of Medical Technology, Department of Internal Medicine, Armed-Force, Taichung General Hospital, Taichung 402, Taiwan, ROC² Laboratory of Exercise Biochemistry, TPEC, Taipei 105, Taiwan, ROC³ Emergency Department, China Medical University Hospital, Taichung 413, Taiwan, ROC⁴ Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung 413, Taiwan, ROC⁵ Department of Healthcare Administration, Asia University, Taichung 413, Taiwan, ROC⁶ Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, ROC⁷ Graduate Institute of Chinese Medical Science, China Medical University, Taichung 404, Taiwan, ROC⁸ Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC⁹ Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan, ROC

(Correspondence should be addressed to C-Y Huang; Email: cyhuang{at}mail.cmu.edu.tw)

^* (W-W Kuo and C-Y Huang contributed equally to this work)

The role played by IGF-II in signal transduction through the IGF-II/mannose-6-phosphate receptor (IGF2R) in heart tissue has been poorly understood. In our previous studies, we detected an increased expression of IGF-II and IGF2R in cardiomyocytes that had undergone pathological hypertrophy. We hypothesized that after binding with IGF-II, IGF2R may trigger intracellular signaling cascades involved in the progression of pathologically cardiac hypertrophy. In this study, we used immunohistochemical analysis of the human cardiovascular tissue array to detect expression of IGF2R. In our study of H9c2 cardiomyoblast cell cultures, we used the rhodamine phalloidin staining to measure the cell hypertrophy and western blot to measure the expression of cardiac hypertrophy markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cells treated with IGF-II. We found that a significant association between IGF2R overexpression and myocardial infarction. The treatment of H9c2 cardiomyoblast cells with IGF-II not only induced cell hypertrophy but also increased the protein level of ANP and BNP. Using Leu27IGF-II, an analog of IGF-II which interacts selectively with the IGF2R, to specifically activate IGF2R signaling cascades, we found that binding of Leu27IGF-II to IGF2R led to an increase in the phosphorylation of protein Kinase C (PKC)- and calcium/calmodulin-dependent protein kinase II (CaMKII) in a Gq-dependent manner. By the inhibition of PKC-/CaMKII activity, we found that IGF-II and Leu27IGF-II-induced cell hypertrophy and upregulation of ANP and BNP were significantly suppressed. Taken together, this study provides a new insight into the effects of the IGF2R and its downstream signaling in cardiac hypertrophy. The suppression of IGF2R signaling pathways may be a good strategy to prevent the progression of pathological hypertrophy.