Bioinformatic profiling of the transcriptional response of adult rat cardiomyocytes to distinct fatty acids

Joseph B. Lockridge, Mary L. Sailors, David J. Durgan, Oluwaseun Egbejimi, William J. Jeong, Molly S. Bray, William C. Stanley, and Martin E. Young

Pediatrics, Baylor College of Medicine, Houston, TX 77030

Corresponding Author: meyoung{at}bcm.edu

Diabetes mellitus, obesity, and dyslipidemia increase risk for cardiovascular disease, and expose the heart to high plasma fatty acid (FA) levels. Recent studies suggest that distinct fatty acid species are cardiotoxic (e.g. palmitate), while others are cardioprotective (e.g. oleate), although the molecular mechanisms mediating these observations are unclear. The purpose of the present study was to investigate the differential effects of distinct fatty acid species (varying carbon length and degree of saturation) on adult rat cardiomyocyte (ARC) gene expression. ARCs were initially challenged with 0.4mM octanoate (8:0), palmitate (16:0), stearate (18:0), oleate (18:1), or linoleate (18:2) for 24 hours. Microarray analysis revealed differential regulation of gene expression by the distinct fatty acids; the order regarding the number of genes whose expression was influenced by a specific fatty acid was octanoate(1188)>stearate(740)>palmitate(590)>oleate(83)>linoleate(65). In general, cardioprotective FAs (e.g. oleate) increased expression of genes promoting FA oxidation to a greater extent than cardiotoxic FAs (e.g. palmitate), while the latter induced markers of endoplasmic reticulum and oxidative stress. Subsequent RT-PCR analysis revealed distinct time- and concentration- dependent effects of these FA species, in gene-specific manners. For example, stearate- and palmitate- mediated ucp3 induction tended to be transient (i.e. initial high induction, followed by subsequent repression), while oleate-mediated induction was sustained. These findings may provide insight as to why diets high in unsaturated FAs (e.g. oleate) are cardioprotective, while diets rich in saturated FAs (e.g. palmitate) are not.

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