| 20331438 |
Perez J, Hill BG, Benevides GA, Dranka BP, Darley-Usmar V: Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor. Biochem J. 2010 Mar 24.
Abnormal smooth muscle cell proliferation is a hallmark of vascular disease. Although growth factors are known to contribute to cell hyperplasia, the changes in metabolism associated with this response, particularly mitochondrial respiration, remain unclear. Given the increased energy requirements for proliferation, we hypothesized that platelet-derived growth factor (PDGF) would stimulate glycolysis and mitochondrial respiration and that this elevated bioenergetic capacity is required for smooth muscle cell hyperplasia. To test this hypothesis, cell proliferation, glycolytic flux, and mitochondrial oxygen consumption were measured after treatment of primary rat aortic smooth muscle cells with PDGF. PDGF increased basal and maximal rates of glycolytic flux and mitochondrial oxygen consumption; enhancement of these bioenergetic pathways led to a substantial increase in the mitochondrial reserve capacity. Interventions with the PI3K inhibitor LY-294002 or the glycolysis inhibitor 2-deoxy-D-glucose abrogated PDGF-stimulated proliferation and prevented augmentation of glycolysis and mitochondrial reserve capacity. Similarly, when L-glucose was substituted for D-glucose, PDGF-dependent proliferation was abolished, as were changes in glycolysis and mitochondrial respiration. Interestingly, lactate dehydrogenase protein levels and activity were significantly increased after PDGF treatment. Moreover, L-lactate substitution for D-glucose was sufficient for increasing the mitochondrial reserve capacity and cell proliferation after treatment with PDGF; these effects were inhibited by the lactate dehydrogenase inhibitor, oxamate. These data suggest that glycolysis, by providing substrates that enhance the mitochondrial reserve capacity, plays an essential role in PDGF-induced cell proliferation, underscoring the integrated metabolic response required for proliferation of VSMC in the diseased vasculature. |
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