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Abstract
Transcription factors LXRs, PPARs, and SREBPs have been implicated in a multitude of physiological and pathological processes including atherogenesis. However, little is known about the regulation of these transcription factors at different stages of atherosclerosis progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to compare the contents of mRNAs in pairs intact-injured aorta fragments taken from the same donors. Only minor changes in LXRα, LXRβ, PPARα, PPARγ, SREBP1, and SREBP2 mRNA levels were found in initial lesions as compared with intact non-diseased tissue. The contents of all mRNAs but SREBP2 mRNA were found to be progressively up-regulated in fatty streaks and fibrous lipoid plaques. These changes were only partially reproduced in cultured macrophages upon lipid loading. Wave-shaped changes in abundance of correlations between given group of mRNAs and 28 atherosclerosis-related mRNA species in the course of atherogenesis were observed. The impact of specific mRNA correlations on the total correlations also significantly varied between different lesion types. The study suggests that the extent and forms of LXR/PPAR/SREBP participation in intima functions vary nonlinear in individual fashion in atherogenesis. We speculate that the observed changes in mRNAs expression and coupling reflect shifts in lipid ligands availability and cellular composition in the course of atherosclerosis progression.
Highlights
Local inflammation and lipid accumulation are two hallmarks of atherosclerosis
To validate the relevancy of glyceraldehyde-3phosphate dehydrogenase (GAPDH) mRNA as reference point, we have analyzed the expression of the additional housekeeping gene, GNB2L1, in intact and injured aorta fragments from several donors
Initial lesions are characterized by the lowest level of involvement of LXR/PPAR/SREBP mRNA group in correlations
Summary
Local inflammation and lipid accumulation are two hallmarks of atherosclerosis. These processes are mutually dependent, so that the final outcome, i.e. plaque formation, is the same for both lipid and inflammatory stimuli (reviewed in [1]). The balance between lipids entrance into vessel wall, their local biosynthesis and degradation, as well as reverse transfer is maintained mainly by oxysterol sensors LXRa,b (liver X receptors alpha, beta), fatty acids sensors PPARa,b/d,c (peroxisome proliferator-activated receptors alpha, beta/delta, and gamma), and SREBP1,2 (sterol response element-binding proteins 1, 2) whose activity is inhibited by cholesterol at the level of post-translational processing (reviewed in [2,3,4,5,6,7]) All these proteins are transcription factors that interact with response elements found in a multitude of genes engaged in lipid turnover including their own genes. Inefficient targeting of modified lipoproteins for degradation was proposed, underlying mechanisms remain uncertain
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