title: Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation.
abstract: 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.
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Salabei
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects*; D020558:GTP Phosphohydrolases; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020574:Proto-Oncogene Proteins c-sis; D052999:Quinazolinones; D000077214:Becaplermin; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
keywords: 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; Metabolism; 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