Transcriptional modulators targeted at fuel metabolism at hypertrophied heart

The transition of nonfailing to failing cardiac hypertrophy cannot be preve nted by current drug regimens. This investigation examined whether possible drug targets have remained unexplored because they do not result in acute improvement of heart function, Of major importance, in this respect, is an inadequate performance of the sarco(endo)plasmic reticulum Ca2+-ATPase (SER CA2), In the present approach, binding sequences within the proximal promot er of SERCA2 are described which may be useful in the development of drugs (i.e., transcriptional modulators) that interfere selectively with the tran scription of genes of the cardiomyocyte. The proximal promoter region of th e SERCA2 genes has a thyroid response element, 9 potential Sp 1-binding sit es (5'-GGGCGG-3', 5'-CCGCCC-3' and 5'-GGGAGG-3'), and an E-box motif (5'-CA CATG-3'), which may function as glucose response elements. This region also has 2 putative fatty-acid response elements (5'-GGGGGA-3'), It is proposed that the beneficial effects of the carnitine palmitoyltransferase-1 inhibi tor etomoxir arise from a shift in fuel metabolism involving glucose respon se elements and/or peroxisomal proliferator-activated receptors, Although t he relative contribution of these DNA regulatory elements remains to be def ined, it appears that they provide the driving force that prevents the decr ease in transcriptional activity of the SERCA2 gene in the hypertrophic hea rt. It is further concluded that etomoxir represents a member of a novel cl ass of transcriptional modulators that improve function of hypertrophied he arts with unimpeded blood flow by modulating gene expression of the cardiom yocyte. (C)1999 by Excerpta Medica, Inc.