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Chan S.H.H.,Center for Translation Research in Biomedical science | Wu K.L.H.,Kaohsiung Veterans General Hospital | Kung P.S.S.,Kaohsiung Medical University | Chan J.Y.H.,Kaohsiung Veterans General Hospital
Hypertension | Year: 2010

Rosiglitazone, a synthetic ligand of transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), possesses a blood pressure-lowering effect beyond insulin sensitizing and glucose lowering. Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of neurogenic vasomotor tone are located, contributes to neural mechanisms of hypertension. Activation of PPAR-γ protects against oxidative stress in RVLM by upregulation of mitochondrial uncoupling protein 2 (UCP2). We tested the hypothesis that oral intake of rosiglitazone exerts a central antihypertensive effect by ameliorating oxidative stress in RVLM via transcriptional upregulation of UCP2 after PPAR-γ activation. In adult spontaneously hypertensive rats but not normotensive Wistar-Kyoto rats, oral intake of rosiglitazone for 1 week resulted in vasodepression and a reduction in the vasomotor components of the systemic arterial pressure spectrum, our experimental index for sympathetic vasomotor tone. These antihypertensive effects of rosiglitazone in spontaneously hypertensive rats were abrogated by microinjection bilaterally into RVLM of PPAR-γ small interfering RNA. Oral intake of rosiglitazone also upregulated UCP2 and ameliorated the heightened superoxide anion level in RVLM of spontaneously hypertensive rats. Protection against oxidative stress in RVLM by rosiglitazone was abrogated by PPAR-γ small interfering RNA or by antisense oligonucleotide against ucp2 mRNA. Gene knockdown of ucp2 in RVLM also reversed the antihypertensive effect of rosiglitazone. These results suggest that oral intake of rosiglitazone promotes a central antihypertensive effect by decreasing sympathetic vasomotor activity through a PPAR-γ-dependent protection against oxidative stress in RVLM via transcriptional upregulation of the mitochondrial UCP2. © 2010 American Heart Association, Inc. Source

Brain stem cardiovascular regulatory dysfunction during brain death is underpinned by an upregulation of nitric oxide synthase II (NOS II) in rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from blood pressure of comatose patients that disappears before brain death ensues. Furthermore, the ubiquitin-proteasome system (UPS) may be involved in the synthesis and degradation of NOS II. We assessed the hypothesis that the UPS participates in brain stem cardiovascular regulation during brain death by engaging in both synthesis and degradation of NOS II in RVLM. In a clinically relevant experimental model of brain death using Sprague-Dawley rats, pretreatment by microinjection into the bilateral RVLM of proteasome inhibitors (lactacystin or proteasome inhibitor II) antagonized the hypotension and reduction in the life-and-death signal elicited by intravenous administration of Escherichia coli lipopolysaccharide (LPS). On the other hand, pretreatment with an inhibitor of ubiquitin-recycling (ubiquitin aldehyde) or ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1) potentiated the elicited hypotension and blunted the prevalence of the life-and-death signal. Real-time polymerase chain reaction, Western blot, electrophoresis mobility shift assay, chromatin immunoprecipitation and co-immunoprecipitation experiments further showed that the proteasome inhibitors antagonized the augmented nuclear presence of NF-κB or binding between NF-κB and nos II promoter and blunted the reduced cytosolic presence of phosphorylated IκB. The already impeded NOS II protein expression by proteasome inhibitor II was further reduced after gene-knockdown of NF-κB in RVLM. In animals pretreated with UCH-L1 inhibitor and died before significant increase in nos II mRNA occurred, NOS II protein expression in RVLM was considerably elevated. We conclude that UPS participates in the defunct and maintained brain stem cardiovascular regulation during experimental brain death by engaging in both synthesis and degradation of NOS II at RVLM. Our results provide information on new therapeutic initiatives against this fatal eventuality. Source

Yang J.-L.,U.S. National Institute on Aging | Yang J.-L.,Center for Translation Research in Biomedical science | Lin Y.-T.,Center for Translation Research in Biomedical science | Chuang P.-C.,Kaohsiung Chang Gung Memorial Hospital | And 2 more authors.
NeuroMolecular Medicine | Year: 2014

Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1. © 2013 Springer Science+Business Media New York (outside the USA). Source

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