IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via Galphaq interaction and protein kinase C-alpha/CaMKII activation in H9c2 cardiomyoblast cells.
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)-alpha and calcium/calmodulin-dependent protein kinase II (CaMKII) in a Galphaq-dependent manner. By the inhibition of PKC-alpha/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.
Chu
Chun-Hsien
CH
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC.
Tzang
Bor-Show
BS
Chen
Li-Mien
LM
Kuo
Chia-Hua
CH
Cheng
Yi-Chang
YC
Chen
Ling-Yun
LY
Tsai
Fuu-Jen
FJ
Tsai
Chang-Hai
CH
Kuo
Wei-Wen
WW
Huang
Chih-Yang
CY
D009320:Atrial Natriuretic Factor / Q000032:analysis*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006801:Humans; D006984:Hypertrophy; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D020097:Natriuretic Peptide, Brain / Q000032:analysis*; D051571:Protein Kinase C-alpha / Q000502:physiology*; D017527:Receptor, IGF Type 2 / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D017527:Receptor, IGF Type 2; D020097:Natriuretic Peptide, Brain; D007335:Insulin-Like Growth Factor II; D009320:Atrial Natriuretic Factor; D051571:Protein Kinase C-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11