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2013 ; 304
(12
): H1624-33
Nephropedia Template TP
Miller MW
; Knaub LA
; Olivera-Fragoso LF
; Keller AC
; Balasubramaniam V
; Watson PA
; Reusch JE
Am J Physiol Heart Circ Physiol
2013[Jun]; 304
(12
): H1624-33
PMID23585138
show ga
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-? coactivator-1?, 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.
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