Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir.

Pressure overload on the heart is known to produce hypertrophy of cardiomyocytes and distinct changes in protein phenotype, including reduced expression of the gene for the sarcoplasmic reticulum (SR) Ca2+ATPase (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 with 8 wk of aortic constriction was prevented by treatment with etomoxir, an inhibitor of carnitine palmitoyltransferase 1. The reduction in steady-state mRNA levels for SR phospholamban (PLP) and Ca2+ release channel (CRC) in the pressure-overloaded animals was also prevented without any reduction in the extent of cardiac hypertrophy by treatment with 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 beneficial 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 mRNA for SR proteins in the hypertrophied heart and thus may prevent the transition of cardiac hypertrophy into heart failure.