ANTITHETICAL ACCUMULATION OF MYOSIN HEAVY-CHAIN BUT NOT ALPHA-ACTIN MESSENGER-RNA ISOFORMS DURING EARLY STAGES OF PRESSURE-OVERLOAD INDUCED RAT CARDIAC-HYPERTROPHY

Myocardial response to a hemodynamic overload involves changes in the expression of isogenes encoding myosin heavy chain (MHC) and actin: beta-MHC/alpha-MHC and skeletal/cardiac alpha-actin mRNA isoform ratios are increased. It is not known whether these changes are due to increased accumulations of the two neosynthesized transcripts, beta-MHC and skeletal alpha-actin, or whether the mRNA isoforms normally present, alpha-MHC and cardiac alpha-actin, are concomitantly decreased. To answer these questions, using dot-blot hybridizations, primer extension, and exonuclease VII mapping assays, we have analyzed the content of sarcomeric MHC and actin mRNAs in the poly(A+) RNA in left ventricles of 23-24-day-old rats 18 and 24 hours after a pressure overload induced by stenosis of the thoracic aorta. The results showed a 1.9-fold increase in poly(A+) RNA after the stenosis. Skeletal/cardiac alpha-actin mRNA isoforms were already increased fivefold (from 0.19 to 0.99) at 18 hours, and this was exclusively due to a 5.5-fold increase in skeletal alpha-actin mRNA. At 24 hours, this ratio was increased ninefold (from 0.14 to 1.22), and this was due to a 4.3-fold increase in the level of skeletal alpha-actin mRNAs (p<0.001) and a 1.9-fold decrease of cardiac alpha-actin mRNA (p<0.001), restoring the same proportion of sarcomeric actin mRNA in sham-operated and operated rats. A significant increase in the beta-MHC/alpha-MHC mRNAs (9.6-fold, from 0.05 to 0.49) was only observed at 24 hours, because of a striking 3.5-fold decrease (p<0.001) in the level of alpha-MHC mRNA, resulting in a 2.6-fold decrease (p<0.001) in total sarcomeric MHC mRNA. These results strongly suggest that, in the early stages of a hemodynamic overload, the genes encoding MHC isoforms are regulated in an antithetical manner, whereas the actin pair is not, since the expression of the skeletal alpha-actin gene was upregulated and that of the cardiac alpha-actin gene was unaffected. Thus, the different sarcomeric components in the same heart are not equivalent targets for the mechanisms activated by changes in external cardiac load.