Cardiac hypertrophy: old concepts, new perspectives.
Growth of the heart in hypertrophy is accompanied by changes in the phenotypic expression of cardiac genes. To explore the molecular basis of cardiac hypertrophy, we have analyzed the regulation of myosin heavy chain gene (MHC) expression. In one set of experiments, pressure overload on the rat heart was produced by constriction of the abdominal aorta. Changes in the alpha and beta-MHC mRNA were then studied in overloaded hearts and following load removal. Pressure overload resulted in down-regulation of the alpha-MHC with corresponding up-regulation of the steady state level of beta-MHC mRNA. Load removal (debanding) resulted in regression of cardiac hypertrophy and a rapid return of alpha-MHC mRNA to normal values. In contrast, the recovery in beta-MHC mRNA was much slower to the extent that it remained substantially elevated compared to respective sham controls even after 7 weeks of post-debanding. These results suggest that putative load-related signals independently regulate two genes. Several lines of evidence indicate that adrenergic nervous system plays an important role in the induction and maintenance of cardiac hypertrophy and in the redistribution of myosin isoforms. We have analyzed the effect of cAMP inducing agents on the regulation of alpha-MHC gene in primary cultures of the fetal (18 day) rat cardiac myocyte. Inclusion of 8 Br-cAMP in the culture media increased the expression of alpha-MHC promoter/reporter construct comprising of 2.9 kb upstream sequence of the alpha-MHC gene. Several deletion mutations in the alpha-MHC gene promoter defined the cAMP responsive boundaries to be a 32 bp region comprising of -71 to -40 bp sequences. Deletion of this region resulted in loss of cAMP response as well as in basal expression of alpha-MHC promoter/reporter construct. These data suggest a role of beta-adrenergic pathway in the modulation of alpha-MHC gene expression.
Gupta
M
M
Heart Institute for Children, Hope Childrens Hospital, Oak Lawn, IL 60463, USA.
Gupta
M P
MP
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains / Q000235:genetics*; D024501:Nonmuscle Myosin Type IIB; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D020409:Molecular Motor Proteins; C491238:Myh9 protein, rat; D012333:RNA, Messenger; D000242:Cyclic AMP; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains