Coronary heart disease:Significance of liver X receptor α genomics

Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease(CHD).In this regard ligand activated liver X receptor(LXR)-α has emerged as a key molecular switch by its inherent ability to modulate an array of genes involved in these two fundamental cellular processes.In addition,LXR-α has also been found to play a role in hepatic lipogenesis and innate immunity.Although several lines of evidence in experimental model systems have established the atheroprotective nature of LXR-α,human subjects have been reported to possess a paradoxical situation in which increased blood cellular LXR-α gene expression is always accompanied by increased coronary occlusion.This apparent paradox was resolved recently by the finding that CHD patients possess a deregulated LXR-α transcriptome due to impaired ligand-receptor interaction.This blood cellular mutated LXR-α gene ex- pression correlated specifically with the extent of coro- nary occlusion and hence need is felt to devise new synthetic ligands that could restore the function of this mutated LXR-αprotein in order to modulate genes involved in reverse cholesterol transport and suppression of the inflammatory response leading to the effective treatment of CHD.

Coronary atherosclerosis:Significance of autophagic armour

Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins.Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer,neurodegeneration,aging and heart failure,a growing body of evidence now reveals a protective role for autophagy in atherosclerosis,mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells.Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

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

AIM: To investigate the role of [breast and ovarian cancer susceptibility 1(BRCA1)-associated RING domain 1(BARD1)]/BRCA1 E3-ubiquitin ligase complex in governing the stability of mutant liver X receptor-(LXR-α) protein in coronary heart disease(CHD) subjects.METHODS: The expression analysis of various genes was carried out by quantitative real time polymerase chain reaction and western blotting within blood mononuclear cells of human CHD subjects at various stages of coronary occlusion and their corresponding normal healthy counterparts.Immunoprecipitation experiments were performed to establish protein interactions between LXR-αand BARD1.Peripheral blood mononuclear cells were cultured and exposed to Vitamin D_3 and Cisplatin to validate the degradation of mutant LXR-αprotein in CHD subjects by BARD1/BRCA1 complex.RESULTS: The expression of mutant LXR-αprotein in CHD subjects was found to decrease gradually with the severity of coronary occlusion exhibiting a strong negative correlation,r =-0.975 at P < 0.001.Further,the expression of BARD1 and BRCA1 also increased with the disease severity,r = 0.895 and 0.873 respectively(P < 0.001).Immunoprecipitation studies established that BARD1/BRCA1 complex degrades mutant LXR-αvia ubiquitination.The absence of functional LXR-αprotein resulted in increased expression of inflammatory cytokines such as interleukin(IL)-6,IL-8 and interferon-and decreased expression of ABCA1(ATP-binding cassette A1)(r = 0.932,0.949,0.918 and-0.902 with respect to Gensini score;P < 0.001).Additionally,cell culture experiments proved that Vitamin D_3 could prevent the degradation of mutant LXR-αand restore its functional activity to some extent.CONCLUSION: Mutant LXR-αprotein in CHD subjects is degraded by BARD1/BRCA1 complex and Vitamin D_3 can rescue and restore its function.

Heart and Brain:A neutro-genomic link

The philosophy of heart and brain are very ancient in our literature where the things good for the heart are not suggested good for the brain and vice-versa.Modern medicine is characterized by a high degree of specialization and the heart-brain connection that could be targeted to treat these complex cardiovascular/brain disorders.The idea that adverse diet/genome interactions can cause disease is not new.In the recent era the science of nutritional genomics have increased our understanding of diet-health-gene interactions and have provided a number of benefits for individuals,groups and societies.Since dietary chemicals are regularly ingested and participate indirectly and directly in regulating gene expression,it follows that a subset of genes regulated by diet must be involved in disease initiation,progression,and severity.In this regards Liver X Receptor(LXR)-a,a key transcription factors,associated with the several chronic pathological situation including coronary heart disease and neurodegenerative diseases have recently been found to be regulated by the dietary components.The crucial findings at molecular biology unit,Post Graduate Institute of Medical Education and Research(PGIMER),Chandigarh,INDIA have not only forced us to explore nutritional genomics as a holistic systems approach to understand the relationship between diet and health,but also to look into the disease preventing and health promoting foods that match our lifestyles,cultures and genetics.After all,we are what we eat.