Although basic pathological, physiological, and signal transduction mechanisms associated with secondary pulmonary hypertension have been elucidated, underlying genes responsible for these phenotypes remain to be discovered. The goal of this study was to identify gene expression profiles in lung parenchyma of rat model during development of pulmonary hypertension induced by left ventricular dysfunction using microarray.
Male Sprague-Dawley rats were divided into two groups: sham-operated control, and surgically induced pulmonary hypertension by partially constricting the abdominal aorta with a silk ligature. The rats were followed by serial echocardiography at 4 weeks, 6 weeks and 28 weeks. Samples of lung RNA was extracted and amplified using MessageAmpTM (Ambion). Gene expression analysis, using competitive hybridization, and dye-swap techniques were performed. Microarray scanning and data acquisition were done with an Axon 4000A scanner and Axon GenePix 5.0 software. Data normalization and bioinformatic analysis was performed with Gene Spring 6.1 software from Silicon Genetics, Inc.
An interrogation of gene lists identified 93 genes up-regulated in lungs of rats with acute diastolic dysfunction (4 weeks), 45 genes up-regulated in pulmonary tissue from rats with compensated hearts (6 weeks) and 69 genes up-regulated in lung tissue from rats with systolic heart failure (28 weeks). An interrogation of gene lists also identified 91 genes down-regulated at 4 weeks, 17 genes at 6 weeks, and 28 genes at 28 weeks.
The study indicates a dynamic changes in the expression of genes in lung tissue secondary to heart failure fall into 4 distinct patterns of gene expressions: 1) Initial gene activation, followed by suppression, then reactivation (Cellular metabolism, structural proteins) 2) Initial gene quiescence, followed by activation, then suppression (Signal transductions, inflammation and immunoregulators, adhesion/extracellular proteins and transport proteins, intracellular transport proteins) 3) Continued increase in gene activation (Transcription regulators) 4) Continued decrease in gene activation (Cell cycle and cell differentiation).
Gene expression profiles using microarry is an important diagnostic and prognostic markers of pulmonary hypertension and could be used to identify new therapeutic targets.
S.M. Hong, None.