Pj. Obrien et al., MYOCARDIAL MESSENGER-RNA CONTENT AND STABILITY, AND ENZYME-ACTIVITIESOF CA-CYCLING AND AEROBIC METABOLISM IN CANINE DILATED CARDIOMYOPATHIES, Molecular and cellular biochemistry, 142(2), 1995, pp. 139-150
Idiopathic dilated cardiomyopathy is associated with derangement of my
ocardial sarcoplasmic Ca-homeostasis and energy production. The molecu
lar mechanism for these changes is unknown. Accordingly, we used genet
ic and experimentally-induced models of canine dilated cardiomyopathy
and tested the hypothesis that these metabolic changes resulted from a
ltered gene expression, as indicated by mRNA content. We studied dilat
ed cardiomyopathy occurring naturally (n=9) in Doberman pinschers, and
in dogs subjected to rapid ventricular pacing (n=5), in comparison wi
th normal dogs (n=9). We determined content and integrity of mRNA's us
ing Northern and slot blotting, and measured activities of their trans
lated product for the Ca-release channel and Ca-ATPase of sarcoplasmic
reticulum, lactate dehydrogenase of glycolysis, citrate synthase of t
he tricarboxylic acid cycle, and for myoglobin, ATP-synthetase and the
adenine nucleotide transporter, which are integral in oxidative phosp
horylation. We found that, whereas both mRNA content and enzyme activi
ty for markers of Ca-cycling, glycolysis, and oxidative phosphorylatio
n were downregulated (20-80%) in dilated cardiomyopathy, they were upr
egulated (10-15%) for tricarboxylic acid cycling and for ribosomal RNA
. RNA from cardiomyopathic tissue was up to 50% more degraded than for
normal hearts in association with a 150% increase in ribonuclease act
ivity. Downregulation of the Ca-cycle was asymmetric, with the Ca-chan
nel being 65% more affected than the Ca-ATPase. This work supports the
general paradigm that transcriptional and translational responses to
pathophysiology are major determinants of the metabolic response seen
in cardiac failure.