MYOCARDIAL MESSENGER-RNA CONTENT AND STABILITY, AND ENZYME-ACTIVITIESOF CA-CYCLING AND AEROBIC METABOLISM IN CANINE DILATED CARDIOMYOPATHIES

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.