Molecular adaptation to pressure overload in human and rat hearts.
The process of enlargement of the heart due to overload involves a significant reconstitution of the organ including myocytes and intracellular constituents. We demonstrated the distribution of two types of cardiac myosin heavy chains (HC alpha and HC beta) in the human heart using monoclonal antibodies. The ventricle comprised mainly HC beta which has low ATPase activity, whereas the atrium was predominantly composed of HC alpha which has high ATPase activity. We also demonstrated isozymic transition of HC alpha to HC beta in the human atrium and ventricle by hemodynamic overload, regarded as a compensatory mechanism to meet an increased demand in work. To examine the molecular mechanism for the expression of these HCs, we have isolated human HC alpha and HC beta cDNA clones from a fetal heart cDNA library. Comparison of the nucleotide and amino acid sequences deduced from the DNA between these cDNA clones showed 91 and 96% homology, respectively. Using HC alpha and HC beta gene-specific sequences, we demonstrated that the transition of HC alpha to HC beta in the overloaded human heart was induced by the expression of HC beta-gene. To determine the role of cellular oncogenes in the process of cardiac growth and hypertrophy, we examined the expression pattern of eight cellular oncogenes during the developmental stage and pressure-overloaded hypertrophy of the rat heart by Northern blot analysis. c-fos, c-myc and c-Ha-ras were expressed in the heart in response to pressure overload and in a stage-specific manner, suggesting that these cellular oncogenes participate in the normal developmental process and hypertrophy of the heart. We also cloned the genes of which expression level was rapidly changed by pressure overload by differential hybridization technique. Our results suggest that clone 4 may be involved in the molecular mechanism for the development of cardiac hypertrophy due to overload.
Yazaki
Y
Y
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Tsuchimochi
H
H
Kurabayashi
M
M
Komuro
I
I
D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D011312:Pressure; D011519:Proto-Oncogenes; D051381:Rats
D004247:DNA; D009218:Myosins