Inhibitors of
carnitine palmitoyl-
transferase I (
CPT I), the key
enzyme for the transport of long-chain
acyl-coenzyme A (
acyl-CoA) compounds into mitochondria, have been developed as agents for treating
diabetes mellitus Type 2. Findings that the
CPT I inhibitor,
etomoxir, has effects on overloaded heart muscle, which are associated with an improved function, were unexpected and can be attributed to selective changes in the dysregulated gene expression of hypertrophied cardiomyocytes. Also, the first clinical trial with
etomoxir in patients with
heart failure showed that
etomoxir improved the clinical status and several parameters of heart function. In view of the action of
etomoxir on gene expression, putative molecular mechanisms involved in an increased expression of SERCA2, the Ca(2+) pump of sarcoplasmic reticulum (SR) and
alpha-myosin heavy chain (MHC) of failing overloaded heart muscle are described. The first 225 bp of human, rabbit, rat and mouse SERCA2 promoter sequence have high identity. Various cis-regularory elements are also given for the promoter of the rat cardiac alpha-MHC gene. It is hypothesised that
etomoxir increases
glucose-
phosphate intermediates resulting in activation of signalling pathway(s) mediated by
phosphatases. Regarding the possible direct action of
etomoxir on
peroxisome proliferator activated receptor alpha (
PPAR-alpha) activation, it could upregulate the expression of various
enzymes that participate in beta-oxidation, thereby modulating some effects of
CPT 1 inhibition. Any development of alternative drugs requires a better understanding of the signal pathways involved in the altered gene expression. In particular, signals need to be identified which are altered in overloaded hearts and can selectively be re-activated by
etomoxir.