title: Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model.
abstract: Diabetes affects more than 330 million people worldwide and causes elevated cardiovascular disease risk. Mitochondria are critical for vascular function, generate cellular reactive oxygen species (ROS), and are perturbed by diabetes, representing a novel target for therapeutics. We hypothesized that adaptive mitochondrial plasticity in response to nutrient stress would be impaired in diabetes cellular physiology via a nitric oxide synthase- (NOS-) mediated decrease in mitochondrial function. Primary smooth muscle cells (SMCs) from aorta of the nonobese, insulin resistant rat diabetes model Goto-Kakizaki (GK) and the Wistar control rat were exposed to high glucose (25 mM). At baseline, significantly greater nitric oxide evolution, ROS production, and respiratory control ratio (RCR) were observed in GK SMCs. Upon exposure to high glucose, expression of phosphorylated eNOS, uncoupled respiration, and expression of mitochondrial complexes I, II, III, and V were significantly decreased in GK SMCs (p < 0.05). Mitochondrial superoxide increased with high glucose in Wistar SMCs (p < 0.05) with no change in the GK beyond elevated baseline concentrations. Baseline comparisons show persistent metabolic perturbations in a diabetes phenotype. Overall, nutrient stress in GK SMCs caused a persistent decline in eNOS and mitochondrial function and disrupted mitochondrial plasticity, illustrating eNOS and mitochondria as potential therapeutic targets.
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Keller
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Knaub
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: P Mason
authors.initials: PM
authors.lastname: McClatchey
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Chelsea A
authors.initials: CA
authors.lastname: Connon
authors.affiliation: Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Bouchard
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Miller
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Geary
authors.affiliation: Department of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.affiliation: Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA; Center for Women's Health Research, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009569:Nitric Oxide