Abstract 1561: Nitric Oxide-Dependent Differential Genes Expression in Septic Shock Induced Myocardial Depression
Myocardial dysfunction is a critical manifestation of septic shock. At the cellular level, reduced myocardial contractility may be induced by both nitric-oxide-dependant and independent mechanisms. To understand the molecular changes characterizing reduction in myocardial contractility we performed microarray analysis on hearts from C57/BL6 wild-type (WT) and iNOS knockout mice after 48 hours of septic shock induced by cecal ligation and perforation (CLP). WT mice showed 25–30% reduction in maximal rates of ventricular contraction and relaxation (i.e. contractility, p<0.001); in contrast iNOS knockout mice were resistant to myocardial depression. Sepsis induced coordinated changes in cardiac gene expression. Significant Analysis of Microarray identified 546 significantly changed genes (False Discovery Rate (FDR) 3%) in myocardial depression in wt animals. In iNOS animals, approximately 160 genes were altered in response to the septic stimulus (FDR 5%). Onto-express was used to identify functional enrichment (p≤0.0003). A new phenotype arises in WT mice, with dramatic increase in the expression of pro-inflammatory, coagulation and protein metabolism related genes and significant down regulation in genes involved in carbohydrate and lipid metabolism. Sepsis is also associated with down-regulation of 38 key mitochondrial genes in the myocardium as well as with isoform switching in the expression of genes for contractile proteins such as myosin heavy chain (MHC). Adult isoform (αMHC) is down regulated (0.6 fold) while fetal isoform (βMHC) is 31 fold up-regulated. Transcriptional response was confirmed by real-time PCR. This molecular switch correlated with changes in left ventricular contractility. In the iNOS deficient animals, where contractile depression was minimal or absent, this switch was not detected, suggesting that molecular switches favoring the expression of fetal isoforms of contraction related proteins are iNOS dependent. Western blot analysis confirmed predicted βMCH and αMHC gene product regulation in septic shock. In summary, myocardial depression may be an adaptive response in survivors of septic shock, favoring energy efficient fetal forms of MHC (βMHC). This molecular switch is mediated by iNOS.