Genomic effect of vitamin ‘C’ and statins within human mononuclear cells involved in atherogenic process

Abstract

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-a (LXR-a), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (a, g) genes and upregulate LXR-a gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-a gene expression was in conformity with the downregulatory effect of LXR-a on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-a-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

Modulation of LXR-α and the effector genes by Ascorbic acid and Statins in psoriatic keratinocytes

“…22-R hydroxycholestrol was more potent in activating LXR-a compared to Ascorbic acid ? 22-ROH cholesterol [11]. An increase of 55 % in LXR-a gene expression at RNA level was observed in Atorvastatin ?…”

“…The present study tries to enlighten the dermatologists about the recently discovered immunomodulatory effects of statins in order to encourage research on the use of these safe and inexpensive agents in the treatment of various immunological dermatologic conditions [21,22]. Keeping this in mind and data accumulated on the activation of LXR-a by Statins [2,23] and Vitamin C [11], made it important for us to do a preliminary test on the effect of these compounds in the psoriatic lesional keratinocytes. Interestingly, the cultured psoriatic keratinocytes treated with both Ascorbic acid and Atorvastatin along with 22-R hydroxycholestrol reverted the characteristics to the normal counterpart, thereby proving the role LXR-a may play in the pathophysiology of psoriasis (Fig.…”

“…The treatment with Atorvastatin (Sigma, PZ0001-5MG) ?22R hydroxycholestrol (Sigma, H9384-1MG) and Ascorbic acid (Sigma, A5960) ?22R hydroxycholestrol was performed. Cells in one of the wells were incubated with 30 lM Atorvastatin, and the other well was treated with 0.2 mg/ml Ascorbic acid for 12 h [11].Then, 10 lM 22R hydroxycholestrol was added to both the wells and cells were then incubated for 48 h at 37°C in 5 % Co 2 -atmosphere. At the end of this incubation period, the cells from each well were harvested by centrifugation at 2509g for 10 min.…”

Blood cellular mutant LXR-α protein stability governs initiation of coronary heart disease

“…LXR-α has been widely recognized as a master gene that plays a crucial role in cholesterol homeostasis, lipid peroxidation and inflammation responsible for the initiation of CHD and its clinical implications [1][2][3][4][5][6][7] . Apart from the observed protective effects of LXR-α agonists in the various cellular and animal model systems [8][9][10][11][12][13][14] , the importance of LXR-α in pathogenesis of CHD is further highlighted by the studies from our laboratory which showed that both statins (drug of choice for CHD) and vitamin C have an inherent capacity to upregulate LXR-α expression [15] and also that human CHD subjects (with or without hyperlipidemia) have conspicuously higher blood cellular LXR-α mRNA expression as compared to their normal healthy counterparts [16] . However, synthetic agonists for the LXR-α activation designed as therapeutic agents for the regression of coronary atherosclerosis did not meet the expected success.…”

“…Several in vitro and in vivo studies in animal models of atherosclerosis have shown that LXR-α agonists can attenuate lesion progression and also lead to regression of an already established plaque [8][9][10][11][12][13][14] . The observation that statins as well as vitamin C, both have an inherent ability to upregulate LXR-α [15] further underline its importance. Findings from our laboratory have demonstrated that both normolipidemic and hyperlipidemic human coronary heart disease (CHD) subjects have significantly higher expression of blood cellular LXR-α as compared to the corresponding controls [16] .…”