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.

SummarySince receptor/transcription factor family especially peroxisome proliferator-activated receptors PPARs (a, c) and liver X receptor a (LXRa) have been recognized to play crucial role in both lipid metabolism and inflammation, the present study was addressed to explore the interrelationship between blood cellular genomic expression profile, serum lipid levels and severity of coronary heart disease (CHD) in human subjects. Based upon the demographic and laboratory data, the human subjects were divided into 4 groups. Genomic expression profile in the subjects belonging to these groups was determined by measuring the transcriptional expression of genes coding for PPARs (a, c), CD36, LXRa and low density lipoprotein receptor (LDLR) in their blood mononuclear cells. This genomic expression profile was correlated with serum lipid profile as well as with the severity of CHD (revealed by coronary angiography coupled with modified Gensini score) using standard statistical analytical methods. Further in vitro and in vivo effect of statins on such genomic profile was also explored. Although genes coding for PPARs (a, c), CD36, LDLR showed correlation with the severity of coronary atherosclerosis , blood cellular LXRa genomic profile showed conspicuous negative correlation with the severity of coronary atherosclerosis in subjects with or without hypercholesterolemia. This view was further confirmed in experiments directed to understand the effect of statins on the cellular genomic profile of PPARs (a, c) and LXRa. Based on these reported findings, we propose that blood cellular LXRa genomic profile has a protective effect against the development of CHD and hence may be of importance in devising synthetic therapeutic drugs for CHD in future.

The present study was addressed to understand as to how the expression of genes, that play crucial role in both inflammation and autoimmune process, within blood mononuclear cells are effected by the molecular mimicry between streptococcal antigen and heart tissue recognized as main contributor towards the genesis of rheumatic heart disease (RHD). Such a study for the first time revealed that as compared to genomic profile within normal blood mononuclear cells, the cells derived from rheumatic heart disease patients exhibited significantly higher expression of genes coding for IL-8, IFN-gamma and CX3CR1 coupled with significant downregulation of CD36 mRNA expression. Based upon these results, we propose that maintenance of such a pathognomonic transcriptome within blood mononuclear cells may be responsible for the initiation and progression of rheumatic heart disease.