The molecular pathways activated in response to acute cathepsin G (CG) exposure, as well as the mechanisms involved in activation of signaling pathways that culminate in myocyte detachment and apoptos Show more
The molecular pathways activated in response to acute cathepsin G (CG) exposure, as well as the mechanisms involved in activation of signaling pathways that culminate in myocyte detachment and apoptosis remain unclear. This study aimed to determine the changes in gene expression patterns associated with time dependent CG exposure to neonatal rat cardiomyocytes (NRCMs). Microarray analysis revealed a total of 451, 572 and 1127 differentially expressed genes after CG exposure at 1, 4 and 8 h respectively. A total of 54 overlapped genes at each time point were mapped by Ingenuity Pathway Analysis (IPA). The top up-regulated genes included Hamp, SMAD6, NR4A1, FOSL2, ID3 and SLAMF7, and down-regulated genes included CYR61, GDF6, Olr640, Vom2r36, DUSP6 and MMP20. Our data suggest that there are multiple deregulated pathways associated with cardiomyocyte death after CG exposure, including JAK/Stat signaling, IL-9 signaling and Nur77 signaling. In addition, we also generated the molecular network of expressed gene and found most of the molecules were connected to ERK1/2, caspase, BCR (complex) and Cyclins. Our study reveals the ability to assess time-dependent changes in gene expression patterns in NRCMs associated with CG exposure. The global gene expression profiles may provide insight into the cellular mechanism that regulates CG dependent myocyte apoptosis. In future, the pathways important in CG response, as well as the genes found to be differentially expressed might represent the therapeutic targets for myocyte survival in heart failure. Show less
Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations Show more
Genome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance. We studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model. We replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10(-7). We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10(-7)), rs10503669 in LPL (beta =-0.18 s.d, p=1.0 x 10(-4)) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10(-4)). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively. We report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations. Show less