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

Abstract

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 FA 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 FA species (varying carbon length and degree of saturation) on adult rat cardiomyocyte (ARC) gene expression. ARCs were initialy challenged with 0.4 mM octanoate (8:0), palmitate (16:0), stearate (18:0), oleate (18:1), or linoleate (18:2) for 24 h. Microarray analysis revealed differential regulation of gene expression by the distinct FAs; the order regarding the number of genes whose expression was influenced by a specific FA was octanoate (1,188) . 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), whereas 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 a gene-specific manner. For example, stearate-and palmitate-mediated ucp3 induction tended to be transient (i.e., initial high induction, followed by subsequent repression), whereas oleate-mediated induction was sustained. These findings may provide insight into why diets high in unsaturated FAs (e.g., oleate) are cardioprotective, whereas diets rich in saturated FAs (e.g., palmitate) are not.

Inflammation at the Molecular Interface of Atherogenesis

“…101,102 For example, oxidants in the diet, vessel wall shear stress, and modified LDL can now be monitored to assess their roles in vascular EC modification and altered gene expression in the vessel wall over time. 100 Mechanisms associated with coronary thrombosis can also be defined via platelet profiling in patients with acute coronary syndromes.…”

Fatty acids regulate perilipin5 in muscle by activating PPARδ

“…Fasting and a HFD can be viewed as contrary physiological conditions with low or excess energy, respectively, but have elevated circulating FAs in common, caused by hormone-stimulated lipolysis of adipose TAG or increased digestion and uptake of FAs. Increased expression of Plins has been observed in various cell types upon stimulation with FAs ( 41,46,61 ), but the molecular mechanisms have been unclear. Our data provide a molecular explanation for regulation of Plin5 in the absence of PPAR ␣ .…”

Is the lack of adiponectin associated with increased ER/SR stress and inflammation in the heart?

“…Advanced age is associated with reduced palmitate oxidation and impaired diastolic function in the heart. [26][27][28] It is known that the IκB family of proteins regulates activation of NFκB by sequestering NFκB in the cytoplasm. The degradation of IκB proteins results in the nuclear entry of NFκB dimmers.…”