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MitoQuinone Rescues Aortic Endothelial Function mediated through eNOS/NO pathway
Author(s) -
Pung YuhFen,
Kmetz John,
Bratz Ian,
Murphy Michael P,
Smith Robin AJ,
Chilian William M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1080.14
Subject(s) - enos , oxidative stress , sodium nitroprusside , chemistry , endothelial dysfunction , nitric oxide , medicine , pharmacology , endocrinology , biochemistry , nitric oxide synthase
Although mitochondrial oxidative stress is known to occur in many models of cardiovascular disease, whether the mitochondrial stressor alone is sufficient to induce endothelial dysfunction, and the underlying mechanisms are unknown. Accordingly, Wistar Kyoto rats (WKY) were divided into 3 groups: Control; Rotenone (Rot): mitochondrial complex I inhibitor infused through Alzet pumps at 1.5 mg/kg, subcutaneously, to induce mitochondrial oxidative stress; MitoQ+Rot: mitochondrial targeted antioxidant, MitoQ, at 50 μM in drinking water to scavenge mitochondrial oxidative stress with Rot for 12 to 14 days. Aortae were collected from Control (n=7), Rot (n=6) and Rot+MitoQ (n=3) groups for functional and molecular analyses. Aortae from controls showed ~53.3% relaxation (isometric vascular ring preparation) in response to acetylcholine (ACh), Rot prevented ACh‐induced dilation suggesting endothelial dysfunction. MitoQ partially reversed the inhibitory effect of Rot (~35.8% vasodilation to ACh) suggesting that mitochondrial oxidative stress is central to this effect. Interestingly, relaxation to sodium nitroprusside (SNP) was greater in the Rot group (~55.1%), than in Control or MitoQ+Rot groups, suggesting that smooth muscle function is not compromised by mitochondrial oxidative stress. To delineate the underlying mechanism(s), enriched aortic ECs fractions were isolated from the groups. To our surprise, activation of eNOS (phosphorylation at s1177) was higher in ECs from Rot, than in Controls and Rot+MitoQ groups (ratio of p‐eNOS to total eNOS: 0.71±0.21 vs 0.44±0.08 and 0.45±0.17, respectively). Similarly, SOD‐2 expression (normalized to porin) was augmented in Rot group, suggesting a possible compensatory mechanism to scavenge excessive mitochondrial superoxide production (Rot: 4.25±0.78, Control: 2.98±0.62 and Rot+MitoQ: 1.38±0.03). Both functional and molecular data imply that mitochondrial oxidative stress uncouples eNOS (activation of eNOS with endothelial dysfunction) and scavenging mitochondrial oxidative stress rescues endothelial function. Collectively our study raises the possibility for mitochondrial therapies as a treatment for vascular disease. Support or Funding Information This work was supported by NIH Grants HL32788, R01 83366, RC1HL100828 (to WMC), American Heart Association Post‐doctoral Fellowship 09POST2290021 and Malaysia Ministry of Higher Education Grant FRGS/1/2015/SKK08/UNIM/03/2 (to YFP).