DOWN-REGULATION OF THE IGF-1 SYSTEM PARALLELS THE ATTENUATION IN THE PROLIFERATIVE CAPACITY OF RAT VENTRICULAR MYOCYTES DURING POSTNATAL-DEVELOPMENT

BACKGROUND: Insulin-Like growth factor-1 receptor (IGF-1R) and its lig and (IGF-1R) have been implicated in the growth of several cell types, including ventricular myocytes. However, the growth-promoting effect of this pathway on myocyte hypertrophy and hyperplasia has not been de termined. During early postnatal development, myocyte cell volume incr eases nearly 25-fold, and myocyte proliferation is markedly attenuated , so a progressive decrease in this signaling mechanism will indicate that the IGF-1-IGF-1R system is mostly involved in cell proliferation. Conversely, a continuous increase in the expression of IGF-1 and IGF- 1R in myocytes with maturation will suggest its involvement in cellula r hypertrophy. DESIGN: Myocytes were isolated from fetal rats and from rats at 1, 5, 11, 21, 35, and 60 days of age. Total RNA was extracted from these cells, and the expression of IGF-1, IGF-2, IGF-1R, and DNA polymerase a was measured by reverse transcriptase-PCR, IGF-1R mRNA l evels were also determined by RNase protection assay, and the changes in IGF-1R protein were determined by the cross-linking technique. Fina lly, the expression of late growth-related genes was determined and co mpared with the fraction of muscle cells synthesizing DNA. These analy ses were restricted to the left ventricular free wall and septum combi ned. RESULTS: Myocardial development was characterized by a progressiv e decrease in the expression of late growth-related genes in myocytes, which was particularly evident at 21 days after birth and persisted u p to 2 months of age. The expression of IGF-2 in these cells decreased at birth, whereas the attenuation in IGF-1 mRNA became apparent a few days later during postnatal development. The induction of IGF-1R at t he message and protein levels decreased by 11 days, and this phenomeno n was more evident at the subsequent age intervals. Moreover, DNA synt hesis in myocytes was sharply reduced at 21 days after birth. CONCLUSI ONS: In conclusion, the decline in myocyte proliferation with cardiac development appears to be coupled with attenuation of the IGF-1-IGF-1R system, which may condition the changes in late growth-regulated gene s, DNA replication, and cellular mitotic division in the myocardium.