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


RESULTS
We 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.


CONCLUSIONS
These 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.
Chen
Zhihong
Z
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. zchen4@partners.org
Ge
Yinlin
Y
Kang
Jing X
JX
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D015536:Down-Regulation; D005822:Genetic Vectors; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016337:RNA, Catalytic; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2