Regulation of cerebral vascular function by sirtuin 1.
OBJECTIVE
Endothelial dysfunction, associated with reduced nitric oxide bioavailability and oxidative stress, is a common feature of vascular-related diseases. Sirtuin 1 (SIRT1) is a protein deacetylase that has been shown to target endothelial nitric oxide synthase in large arteries and is protective during oxidative stress. However, within resistance-sized vessels, the expression and functional effects of SIRT1 remain unknown.


METHODS
Immunoblotting and immunohistochemistry were used to determine SIRT1 expression and localization in cultured brain endothelial cells and intact rat middle cerebral artery. The influence of SIRT1 on vascular function was then studied in intact middle cerebral arteries using pressure myography.


RESULTS
We report for the first time that SIRT1 is expressed in the resistance-sized vessels in the brain and is present in both the endothelium and smooth muscle. Pharmacological inhibition of SIRT1 demonstrated reduced endothelium-dependent dilation mediated by nitric oxide. However, endothelium-independent dilations were comparable in the presence and absence of SIRT1 block.


CONCLUSIONS
Our results support a role for SIRT1 in endothelium-dependent relaxation in the cerebral vasculature and reveal a potential for SIRT1 as a therapeutic target in vascular-related diseases by restoring endothelial function.
Disciplines of Medical Biotechnology             Human Physiology, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
Negara
N
Tajbakhsh
Elke M
EM
Sokoya
D000818:Animals; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014664:Vasodilation / Q000502:physiology*
D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1