Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation.
Vascular smooth muscle cells (VSMCs) develop a highly proliferative and synthetic phenotype in arterial diseases. Because such phenotypic changes are likely integrated with the energetic state of the cell, we hypothesized that changes in cellular metabolism regulate VSMC plasticity. VSMCs were exposed to platelet-derived growth factor-BB (PDGF) and changes in mitochondrial morphology, proliferation, contractile protein expression, and mitochondrial metabolism were examined. Exposure of VSMCs to PDGF resulted in mitochondrial fragmentation and a 50% decrease in the abundance of mitofusin 2. Synthetic VSMCs demonstrated a 20% decrease in glucose oxidation, which was accompanied by an increase in fatty acid oxidation. Results of mitochondrial function assays in permeabilized cells showed few changes due to PDGF treatment in mitochondrial respiratory chain capacity and coupling. Treatment of VSMCs with Mdivi-1-an inhibitor of mitochondrial fission-inhibited PDGF-induced mitochondrial fragmentation by 50% and abolished increases in cell proliferation; however, it failed to prevent PDGF-mediated activation of autophagy and removal of contractile proteins. In addition, treatment with Mdivi-1 reversed changes in fatty acid and glucose oxidation associated with the synthetic phenotype. These results suggest that changes in mitochondrial morphology and bioenergetics underlie the hyperproliferative features of the synthetic VSMC phenotype, but do not affect the degradation of contractile proteins. Mitochondrial fragmentation occurring during the transition to the synthetic phenotype could be a therapeutic target for hyperproliferative vascular disorders.
['Salabei|Joshua K|JK|', 'Hill|Bradford G|BG|']
D000818:Animals D000077214:Becaplermin D049109:Cell Proliferation D002478:Cells, Cultured D004734:Energy Metabolism D020558:GTP Phosphohydrolases D008297:Male D008565:Membrane Proteins D063154:Mitochondrial Dynamics D024101:Mitochondrial Proteins D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D020574:Proto-Oncogene Proteins c-sis D052999:Quinazolinones D051381:Rats D017207:Rats, Sprague-Dawley
Metabolism ADP, adenine dinucleotide phosphate ATP5A1, ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide Atherosclerosis CPT1, carnitine palmitoyl transferase 1 DMEM, Delbucco's Eagle Modified Medium Drp1, dynamin-related protein 1 EDTA, ethylenediaminetetraacetic acid EGTA, ethylene glycol tetraacetic acid Extracellular flux FBS, fetal bovine serum FCCP, Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone Fis1, mitochondrial fission 1 protein Fusion HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid LC3, (microtubule-associated protein 1 light chain 3) MOPS, 3-(N-morpholino)propanesulfonic acid NDUFB8, NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8 NP-40, noniodet P40 Opa1, optic atrophy 1 Oxidative phosphorylation PCNA, proliferating cell nuclear antigen PDGF-BB, platelet-derived growth factor-BB PVDF, polyvinylidene fluoride Restenosis SDHB, succinate dehydrogenase subunit B SDS, sodium dodecyl sulfate TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine VSMC, vascular smooth muscle cells