The Myosin Gene Switching in Human Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is associated with qualitative as well as quantitative changes in myocardial cells. To analyze the molecular basis of isozymic transitions of cardiac myosins in response to pressure overload, we have constructed and characterized two types of myosin heavy chain (MHC) cDNA clones, specifying α-and β-MHCs, and two types of myosin alkali light chain cDNA clones, complementary to atrial type (ALCI) and ventricular type (VLC1) mRNAs from a human fetal heart cDNA library. Using the SI nuclease mapping procedure, we showed that the MHC isozymic transitions from α-to β-MHC in the pressure overloaded atria are produced by changes in the relative level of α-and β-MHC gene expression. In addition, we observed that the expression of VLC1 gene is also induced in the atria subjected to severe pressure overload. Thus, it appears that the increased expression of VLC1 gene, together with the isogene switch from α-to β-MHC gene, may participate in the adaptation of myocardium to new functional requirement. Then, to get a better understanding of the genetic mechanisms involved in the regulation of isogene expression, we have isolated and sequenced genomic clone for VLC1 isoform. Sequence analysis has identified multiple potential cis regulatory elements within a 686-bp upstream region. This region includes 28-bp alternating purine/pyrimidine sequences and two segment exhibiting homology to consensus sequence proposed for viral and cellular enhancer elements. In particular, a comparison of the VLC1 upstream gene sequence with those available for sevaral muscle-specific genes revealed that CC(A + T-rich)6GG elements and CATTCCT sequence are conserved. These results suggested that CArG box (' 96 to '87) has an important role in the positive regulation of the VLC1 gene and this element may be involved in the co-regulation of VLC1 and cardiac α-actin genes. © 1990, The Japanese Circulation Society. All rights reserved.