AJP - Heart and Circulatory Physiology, Vol 251, Issue 5 1017-H1023, Copyright © 1986 by American Physiological Society
Sarcoplasmic reticulum dysfunction: phospholipid alterations induced by lysosomal phospholipase C
R. Franson, D. Gamache, W. Blackwell, D. Eisen and M. L. Hess
Previous work has demonstrated that myocardial ischemia results in a
breakdown of the excitation-contraction coupling system of cardiac muscle
associated with lysosomal activation. It has been hypothesized that
lysosomal activation during the course of myocardial ischemia is mediated
by the production of oxygen free radicals. We have tested the hypothesis
that myocardial ischemia results in the activation of lysosomal
phospholipase C and disruption of calcium transport in sarcoplasmic
reticulum (SR) mediated by oxygen free radicals. Three groups of dogs were
studied: sham-operated controls (n = 6); normothermic global ischemia of
30-min duration (n = 6); and 30 min of normothermic global ischemia
pretreated with intracoronary superoxide dismutase (SOD, 10 micrograms/ml)
plus catalase (25 micrograms/ml). In vitro, isolated SR demonstrated a
significant depression of calcium uptake rates and Ca2+-stimulated,
Mg2+-dependent ATPase activity at both pH 7.0 and 6.4 with the depression
at pH 6.4 greater than 7.0. This depression of SR function was
significantly inhibited in hearts pretreated with SOD plus catalase. In
sham-operated controls, acid-induced dysfunction was associated with
substantial loss of phospholipid phosphorus and major changes in
phospholipid composition. SR contained an extremely active, ion-independent
sphingomyelinase-phospholipase C (SM-PLC) that had maximal activity at pH
4.5-5.0. This SM-PLC was activated when control SR was incubated at acid pH
and the specific activity of SM-PLC was decreased 50% in SR isolated from
normothermic global ischemia. Activity remained at control levels in hearts
pretreated with SOD plus catalase.(ABSTRACT TRUNCATED AT 250 WORDS)
