MODIFICATION OF SARCOPLASMIC-RETICULUM GENE-EXPRESSION IN PRESSURE-OVERLOAD CARDIAC-HYPERTROPHY BY ETOMOXIR

Pressure overload on the heart is known to produce hypertrophy of card iomyocytes and distinct changes in protein phenotype, including reduce d expression of the gene for the sarcoplasmic reticulum (SR) Ca(2+)ATP ase (SERCA2). In this study we have shown that the decrease in SERCA2 gene expression (normalized by poly(A)+ mRNA or 18 S rRNA) in rats wit h 8 wk of aortic constriction was prevented by treatment with etomoxir , an inhibitor of carnitine palmitoyltransferase 1. The reduction in s teady-state mRNA levels for SR phospholamban (PLP) and Ca2+ release ch annel (CRC) in the pressure-overloaded animals was also prevented with out any reduction in the extent of cardiac hypertrophy by treatment wi th etomoxir, Although no changes in mRNA levels for GAPDH were evident in rats with pressure overload, the expression of the alpha-skeletal actin was increased; this change was prevented by etomoxir. Similar be neficial effects of etomoxir treatment were also evident when the gene expression for SR SERCA2, PLP, and CRC in the hypertrophied heart was normalized with respect to mRNA for GAPDH, These results support the view that drugs such as etomoxir may increase the abundance of, the mR NA for SR proteins in the hypertrophied heart and thus may prevent the transition of cardiac hypertrophy into heart failure.