Myosin isoenzymes in normal and hypertrophied human ventricular myocardium.

Abstract

We tested the hypothesis that hypertrophy of the human heart is associated with the redistribution of ventricular isomyosins. Human cardiac myosin was isolated from autopsy samples of left ventricular free wall of patients with cardiac hypertrophy and of fetal, young, and adult subjects without heart disease. The following parameters were studied: electrophoretic migration in denaturing and non-denaturing conditions; immunological cross-reactivities with three different types of antibodies; and early phosphate burst size and steady state ATPase activities stimulated by K+-EDTA, Ca++, Mg++, and actin. The antibodies were chosen for their ability to recognize selectively the rat V1 and V3 cardiac isomyosins. The first type was a monoclonal antibody, CCM-52, prepared against embryonic chick cardiac myosin, the second was an anti-beef atrial myosin, and the third was an anti-rat V1 myosin. CCM-52 reacted with a greater affinity with rat V3 than with rat V1, and was a probe of mammalian V3. Anti-beef atrial myosin and anti-rat V1 myosin both recognized specifically beef atrial and rat V1 myosins, and were thus considered as probes of mammalian V1. Under non-denaturing conditions, human myosins migrated as rat V3 isomyosin; under denaturing conditions, no difference was observed in any of the electrophoretic parameters between all samples tested, except for the fetal hearts which contained a fetal type of light chain. The immunological studies indicated that human myosins were composed mostly of a V3 type (HV3), but contained also some V1 isomyosin. A technique was developed to quantify the amount of human VI isomyosin which was found to range from almost 0 to 15% of total myosin, and to vary from one heart to the other, regardless of the origin of the heart. Enzymatic studies showed no significant difference between normal, hypertrophied, and fetal hearts in any of the activities tested. However, there was a significant correlation between Ca++-stimulated ATPase activities and HV1 amount (at 0.05 M KCl, n = 18, r2 equal 0.49, P less than 0.01; at 0.5 M KCl, n = 18, r 2 = 0.5, P less than 0.01). These data demonstrate the heterogeneity of human ventricular myosin, which appears to be composed, as in other mammalian species, of V1 and V3 isoforms of different ATPase activities (V1 greater than V3). However it seems that V1 to V3 shifts do not appear to be of physiological significance in the adaptation of human heart to chronic mechanical overloads.

Cardiac remodelling: General aspects and mechanisms

“…It is noted that an important change in the phenotype of the hypertrophied heart is the transition of the expression of myosin heavy chain (MHC) gene expression. Under physiological conditions, α-MHC, which promotes faster shortening velocity of cardiac myofibres due to high ATPase activity, is predominant (38,42). On the other hand, in HF, there is a downregulation of α-MHC and upregulation of β-MHC, which is expressed in fetal genes, with less ATPase activity (39,40,41,42).…”

“…Under physiological conditions, α-MHC, which promotes faster shortening velocity of cardiac myofibres due to high ATPase activity, is predominant (38,42). On the other hand, in HF, there is a downregulation of α-MHC and upregulation of β-MHC, which is expressed in fetal genes, with less ATPase activity (39,40,41,42). It has been shown that there is a correlation between the expression of β-MHC and the degree of cardiac hypertrophy (43).…”

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

“…Several investigators have reported an increase in β-MHC and a decrease in the α-MHC isoform in the hypertrophied ventricle in rats (31,32) and humans (33), and found that the expression of β-MHC at the mRNA level is closely correlated with the degree of cardiac hypertrophy (31,34). However, during MHC expression, transcriptional activity does not necessarily reflect mRNA or protein levels.…”

Molecular and cellular mechanisms of cardiotoxicity.

“…Upregulation of these fetal protein isoforms is associated with downregulation of the corresponding adult isoforms, α-MHC and α-cardiac actin (96). These molecular processes are correlated with the development of hypertrophy and the thickness of the ventricular wall, which has been shown to result from an increase in cell size due to an increase in the number of sarcomeres and mitochondria within the cell (97).…”