Down-regulation of the M6P/IGF-II receptor increases cell proliferation and reduces apoptosis in neonatal rat cardiac myocytes

Zhihong Chen,Jing X Kang,Yinlin Ge

doi:10.1186/1471-2121-5-15

Zhihong Chen, Jing X Kang + Show 1 more

Open Access

https://doi.org/10.1186/1471-2121-5-15

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Abstract

BackgroundThe mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) is a multi-functional protein that has been implicated in regulation of cell growth and apoptosis. Cardiac myocytes express relatively high levels of M6P/IGF2R, and cardiomyocyte apoptosis has been identified in a variety of cardiovascular disorders, such as myocardial infarction and heart failure. However, involvement of M6P/IGF2R in the pathogenesis of these conditions has not been determined. Thus, the objective of this study was to determine the role of M6P/IGF2R in regulation of cardiac myocyte growth and apoptosis.ResultsWe down-regulated the expression of M6P/IGF2R in neonatal rat cardiac myocytes and examined the effect on cell proliferation and apoptosis. Infection of neonatal cardiomyocytes with an adenovirus expressing a ribozyme targeted against the M6P/IGF2R significantly reduced the level of M6P/IGF2R mRNA, as determined by RT-PCR and Ribonuclease Protection Assay (RPA). M6P-containing protein binding and endocytosis as well as the M6P/IGF2R-mediated internalization of 125I-IGF-II were lower in the ribozyme-treated cells than the control myocytes, indicating that the number of functional M6P/IGF2R in the ribozyme treated cells was reduced. Accordingly, a marked increase in cell proliferation and a reduced cell susceptibility to hypoxia- and TNF-induced apoptosis were observed in the ribozyme-treated cells.ConclusionsThese findings suggest that M6P/IGF2R may play a role in regulation of cardiac myocyte growth and apoptosis. Down regulation of this gene in cardiac tissues might be a new approach to prevention of cell death or promotion of mitogenesis for certain heart diseases.

Highlights

The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) is a multi-functional protein that has been implicated in regulation of cell growth and apoptosis
The M6P/IGF2R participates in internalization and lysosomal degradation of IGF-II, a mitogen normally acting through the insulin-like growth factor-I (IGF-I) receptor to stimulate cell proliferation [2]
A number of factors involved in cardiomyocyte apoptosis are currently known and include insulin-like growth factor-I (IGF-I), stress-activated protein kinases (SAPKs) and the anti-apoptotic Bcl-2 family [8]

Summary

Introduction

The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) is a multi-functional protein that has been implicated in regulation of cell growth and apoptosis. Morphological and biochemical markers of apoptosis have been identified in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure. This suggests that activation of apoptotic pathways contributes to cardiomyocyte loss and subsequent cardiac dysfunction in these conditions. A number of factors involved in cardiomyocyte apoptosis are currently known and include insulin-like growth factor-I (IGF-I), stress-activated protein kinases (SAPKs) and the anti-apoptotic Bcl-2 family [8]. These potential factors and their corresponding mechanisms have not been identified

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