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.