title: Nitric oxide regulates vascular adaptive mitochondrial dynamics.
abstract: Cardiovascular disease risk factors, such as diabetes, hypertension, dyslipidemia, obesity, and physical inactivity, are all correlated with impaired endothelial nitric oxide synthase (eNOS) function and decreased nitric oxide (NO) production. NO-mediated regulation of mitochondrial biogenesis has been established in many tissues, yet the role of eNOS in vascular mitochondrial biogenesis and dynamics is unclear. We hypothesized that genetic eNOS deletion and 3-day nitric oxide synthase (NOS) inhibition in rodents would result in impaired mitochondrial biogenesis and defunct fission/fusion and autophagy profiles within the aorta. We observed a significant, eNOS expression-dependent decrease in mitochondrial electron transport chain (ETC) protein subunits from complexes I, II, III, and V in eNOS heterozygotes and eNOS null mice compared with age-matched controls. In response to NOS inhibition with NG-nitro-L-arginine methyl ester (L-NAME) treatment in Sprague Dawley rats, significant decreases were observed in ETC protein subunits from complexes I, III, and IV as well as voltage-dependent anion channel 1. Decreased protein content of upstream regulators of mitochondrial biogenesis, cAMP response element-binding protein and peroxisome proliferator-activated receptor-γ coactivator-1α, were observed in response to 3-day L-NAME treatment. Both genetic eNOS deletion and NOS inhibition resulted in decreased manganese superoxide dismutase protein. L-NAME treatment resulted in significant changes to mitochondrial dynamic protein profiles with decreased fusion, increased fission, and minimally perturbed autophagy. In addition, L-NAME treatment blocked mitochondrial adaptation to an exercise intervention in the aorta. These results suggest that eNOS/NO play a role in basal and adaptive mitochondrial biogenesis in the vasculature and regulation of mitochondrial turnover.
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Miller
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Knaub
authors.forename: Luis F
authors.initials: LF
authors.lastname: Olivera-Fragoso
authors.forename: Amy C
authors.initials: AC
authors.lastname: Keller
authors.forename: Vivek
authors.initials: V
authors.lastname: Balasubramaniam
authors.forename: Peter A
authors.initials: PA
authors.lastname: Watson
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001343:Autophagy; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D006579:Heterozygote; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D045222:Electron Transport Chain Complex Proteins; D047495:PPAR gamma; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D050995:Voltage-Dependent Anion Channel 1; D019331:NG-Nitroarginine Methyl Ester
keywords: endothelial nitric oxide synthase; vascular mitochondria