Project description:Role of p300 in regulation of stress-response genes in heart is not clear. Treatment with anti-cancer drug Doxorubicin causes cardiotoxicity through generation of oxidative stress in cardiac myocytes. Loss of p300 enhances cell death and apoptosis in response to Doxorubicin. The objective of this study was to determine if expression of genes regulated by oxidative stress is dependent of presence of p300. Further we investigated if protective effect of p300 against Doxorubicin was due to gene expression effects of p300. We used microarray to compare the transcriptomes of cardiac myocytes transfected with anti-p300 or non-silencing siRNA beforebefore and after exposure to Doxorubicin.
Project description:Right ventricular heart failure (RVF) associated with pulmonary hypertension (PH) is characterized by a distinct gene expression pattern when compared with functional compensatory hypertrophy. Carvedilol treatment after RVF has been established reduces right ventricle (RV) hypertrophy and improves the RV function. In addition, carvedilol treatment has been shown to alter the gene expression of select genes. We sought to identify, on a genome-wide basis, the effect of carvedilol on gene expression. RVF was induced in male Sprague-Dawley rats by the combination of VEGF-receptor blockade and chronic hypoxia; thereafter, one group was treated with carvedilol. RNA was isolated from the RV and subjected to microarray analysis. A prediction analysis of the carvedilol-treated RVs showed that carvedilol treated RVs most resembled in their expression pattern the RVF pattern. However, an analysis beyond the boundaries of the prediction set revealed a small set of genes associated with carvedilol reversal of RVF. Pathway analysis of this set of genes revealed expression changes of genes involved in cardiac hypertrophy, mitochondrial dysfunction, protein ubiquitination, and sphingolipid metabolism. Genes encoding proteins in the cardiac hypertrophy and protein ubiquitination pathways were downregulated in the RV by carvedilol, while genes encoding proteins in the mitochondrial dysfunction and sphingolipid metabolism pathways were upregulated by carvedilol.
