Circulation, Vol 85, 1720-1733, Copyright © 1992 by American Heart Association
SS Margossian, HD White, JB Caulfield, P Norton, S Taylor and HS Slayter
BACKGROUND. A number of parameters reflecting the effects of idiopathic
dilated cardiomyopathy (IDC) on the structure and function of myosin from
the human myocardium were analyzed. METHODS AND RESULTS. The content of the
regulatory light chain, LC2, was reduced in myopathic heart myosin in
contrast to the controls in which it was present in stoichiometric amounts
relative to the essential light chain, LC1. In IDC hearts, the absence or
significant reduction in amount of LC2 was related to the presence of an
active protease, which was isolated and purified about 130-fold. The
protease exhibited a significant degree of specificity: It cleaved LC2
almost totally (but not the heavy chains) in human control heart myosin but
only partially cleaved LC2 in canine heart or in rabbit skeletal muscle
myosins. The protease was present at a very low level or was inactive in
control heart tissue. When the LC1/LC2 molar ratio was calculated, it was
found to be 1:1.0 in control heart myosin and remained constant in various
samples analyzed, whereas in myopathic myosin from different individuals,
this ratio varied from 1:0.1 to 1:0.69. The rates of ATP binding to control
and myopathic myosins were similar, whereas the Vm of actin-activated
ATPase of myopathic myosin was about 25% less than that of the control.
However, ATP binding and its hydrolysis by control S1, i.e., the myosin
head, were faster by a factor of 2 than that of the myopathic S1. In
addition, control myosin synthetic thick filament length as well as
turbidity in solution, measured by light scattering, were twice as large as
those of the myopathic heart myosin. These effects induced by myopathy in
both filament assembly and turbidity were reversed upon reassociation of
IDC myosin with LC2. CONCLUSIONS. The changes in myosin structure and
function were linked to a protease-mediated cleavage of LC2 in myosin; a
possible role for the protease in the degenerative effects of idiopathic
dilated cardiomyopathy is thus defined.
ARTICLES
Light chain 2 profile and activity of human ventricular myosin during dilated cardiomyopathy. Identification of a causal agent for impaired myocardial function
Department of Orthopedic Research, Montefiore Medical Center, Bronx, N.Y. 10467.
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