Abstract
Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47phox). In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47 phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds.
Highlights
The sirtuins are a highly conserved family of enzymes that regulate lifespan in lower organisms
We observed the presence of sirtuin 1 (SIRT1) in dopaminergic neurons and glial cells in the substantia nigra of rodents and in primary mesencephalic cultures and cell lines of dopaminergic and microglial cells
We have shown that SIRT1-induced downregulation of the AII type-1 receptor (AT1)/ NADPH-oxidase axis constitutes an important additional mechanism to counteract OS and inflammation
Summary
The sirtuins are a highly conserved family of enzymes that regulate lifespan in lower organisms. SIRT1 and pharmacological SIRT1 activators such as resveratrol (RV) have been suggested to counteract the effects of aging [7,8,9]. The effects of SIRT1 on brain senescence and the development of neurodegenerative diseases are not clear [12,13,14]. SIRT1activating compounds such as resveratrol and quercetin exert neuroprotective effects on dopaminergic neurons in PD models [15, 16]. It was not clear whether the antioxidant or sirtuin-activating effect (or both) was www.impactjournals.com/oncotarget responsible for the effects of resveratrol [15]. More recent studies have shown that the effect of SIRT1 on the microglial neuroinflammatory response plays a major role in the protective effects of resveratrol [16,17,18]
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