Differential Transcriptome Profile and Exercise Capacity in Cardiac Remodeling by Pressure Overload versus Volume Overload
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BACKGROUND We compared the gene expression profiles in the hypertrophied myocardium of rats subjected to pressure overload (PO) and volume overload (VO) using DNA chip technology, and compared the effects on exercise capacity with a treadmill test. METHODS Constriction of the abdominal aorta or mitral regurgitation induced by a hole in the mitral leaflet were used to induce PO (n = 19), VO (n = 16) or PO + VO (n = 20) in rats. Serial echocardiographic studies and exercise were performed at 2-week intervals, and invasive hemodynamic examination by a pressure-volume catheter system was performed 12 weeks after the procedure. The gene expression profiles of the left ventricle (LV) 12 weeks after the procedure were analyzed by DNA chip technology. RESULTS In hemodynamic analyses, the LV end-diastolic pressure and the end-diastolic pressure-volume relationship slope were greater in the PO group than in the VO group. When we compared LV remodeling and exercise capacity, cardiac fibrosis and exercise intolerance developed in the PO group but not in the VO group (exercise duration, 434.0 ± 80.3 vs. 497.8 ± 49.0 seconds, p < 0.05, respectively). Transcriptional profiling of cardiac apical tissues revealed that gene expression related to the inflammatory response and cellular signaling pathways were significantly enriched in the VO group, whereas cardiac fibrosis, cytoskeletal pathway and G-protein signaling genes were enriched in the PO group. CONCLUSIONS We found that many genes were regulated in PO, VO or both, and that there were different regulation patterns by cardiac remodeling. Cardiac fibrosis and cytoskeletal pathway were important pathways in the PO group and influenced exercise capacity. Cardiac fibrosis influences exercise capacity before LV function is reduced.
Abstract
BACKGROUND We compared the gene expression profiles in the hypertrophied myocardium of rats subjected to pressure overload (PO) and volume overload (VO) using DNA chip technology, and compared the effects on exercise capacity with a treadmill test. METHODS Constriction of the abdominal aorta or mitral regurgitation induced by a hole in the mitral leaflet were used to induce PO (n = 19), VO (n = 16) or PO + VO (n = 20) in rats. Serial echocardiographic studies and exercise were performed at 2-week intervals, and invasive hemodynamic examination by a pressure-volume catheter system was performed 12 weeks after the procedure. The gene expression profiles of the left ventricle (LV) 12 weeks after the procedure were analyzed by DNA chip technology. RESULTS In hemodynamic analyses, the LV end-diastolic pressure and the end-diastolic pressure-volume relationship slope were greater in the PO group than in the VO group. When we compared LV remodeling and exercise capacity, cardiac fibrosis and exercise intolerance developed in the PO group but not in the VO group (exercise duration, 434.0 ± 80.3 vs. 497.8 ± 49.0 seconds, p < 0.05, respectively). Transcriptional profiling of cardiac apical tissues revealed that gene expression related to the inflammatory response and cellular signaling pathways were significantly enriched in the VO group, whereas cardiac fibrosis, cytoskeletal pathway and G-protein signaling genes were enriched in the PO group. CONCLUSIONS We found that many genes were regulated in PO, VO or both, and that there were different regulation patterns by cardiac remodeling. Cardiac fibrosis and cytoskeletal pathway were important pathways in the PO group and influenced exercise capacity. Cardiac fibrosis influences exercise capacity before LV function is reduced.
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