Posttranscriptional Modification of Myosin Heavy-Chain Gene Expression in the Hypertrophied Rat Myocardium

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 8; pp. 3468 - 3472
• Main Authors: OJAMAA, K, PETRIE, J. F, BALKMAN, C, HONG, C, KLEIN, I
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 12.04.1994; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiomegaly - genetics; Cardiovascular disease; Gene expression; Gene Expression Regulation; Genes; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hemodynamics; Hypertrophy; Male; Medical sciences; Messenger RNA; Myocardium; Myocardium - metabolism; Myosins - genetics; Plasmids; Promoter Regions, Genetic; Protein isoforms; Proteins; Rats; Rats, Inbred Lew; RNA; RNA, Messenger - genetics; Rodents; Time Factors; Transcription, Genetic; Heart; Heavy peptide chain; Rat; Transcription; Pathogenesis; Rodentia; Contractile protein; Cardiovascular disease; Posttranscriptional modification; Vertebrata; Experimental disease; Regulation(control); Mammalia; Heart disease; Animal; Myosin; Hypertrophy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.8.3468

Hypertrophy of the myocardium in response to pressure or volume overload elicits a change in myofibrillar protein content as a result of changes in both transcriptional and translational regulation of gene expression. Hemodynamic overload caused by aortic constriction produced changes in the expression of the two isoforms of myosin heavy chain (MHC) with a 319% increase in β-MHC mRNA and a 54% decrease in α-MHC mRNA (P < 0.01). Cardiac unloading as a result of heterotopic transplantation resulted in a decrease in cardiac mass and a similar shift in MHC isoform expression. In this study. We investigated cardiac gene transcription to understand how different hemodynamic stimuli produce similar cardiac phenotypes. We studied the in vivo activity of the α-MHC promoter (-2564 to +421 bp of the transcriptional start site) by directly injecting a recombinant expression plasmid (pAM3LUC) into the ventricular tissue of coarctated animals as well as into the unloaded heterotopic transplanted heart. When expressed as a function of the activity of a constitutively active viral promoter (pSVCAT), pAM3LUC activities were 18.4 ± 2.9, 24.6 ± 2.6, and 25.0 ± 4.5 (x104) luciferase/chloramphenicol acetyltransferase units in the hypertrophied ventricles of 2-, 3-, and 7-day coarctated animals, respectively. These values were not statistically different from pAM3LUC activity in control hearts of sham operated animals even though α-MHC mRNA content was decreased by 54% in the hypertrophied myocardium. This disparity between transcriptional activity and mRNA content suggests that α-MHC expression in the hypertrophic ventricle is in part regulated by a posttranscriptional mechanism. In contrast, α-MHC promoter activity in the unloaded transplanted hearts decreased significantly by 37% compared to control working hearts and suggests that a transcriptional mechanism of regulation of the α-MHC gene may account for the phenotypic expression observed in the unloaded myocardium.