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1.  Effect of angiotension II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats 
Journal of hypertension  2015;33(7):1401-1410.
Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex. In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats. Using Ang II 125I radioimmunoassay, real-time RT-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor (AT1R) in nodose ganglia (NG) from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the NG decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an AT1R antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nM) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μM) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons. These results suggest that elevation of endogenous Ang II in the NG contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels.
doi:10.1097/HJH.0000000000000563
PMCID: PMC4702522  PMID: 25827427
Angiotensin II; autonomic nervous system; baroreceptor neuron; baroreflex sensitivity; heart failure; nodose ganglia; patch-clamp; sodium channel
2.  In-vivo transfection of manganese superoxide dismutase gene or NFκB shRNA in nodose ganglia improves aortic baroreceptor function in heart failure rats 
Hypertension  2013;63(1):88-95.
Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in the patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of NFκB in the sodium channel dysfunction and evaluated the effects of in-vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF rats. CHF was developed at 6–8 weeks after left coronary artery ligation in adult rats. Western bolt and chromatin immunoprecipitation data showed that phosphorylated NFκB p65 and ability of NFκB p65 binding to the sodium channel promoter were increased in the nodose ganglia from CHF rats. In-vivo transfection of adenoviral manganese superoxide dismutase gene or lentiviral NFκB p65 shRNA into the nodose ganglia partially reversed CHF-reduced sodium channel expression and cell excitability in the baroreceptor neurons and improved CHF-blunted arterial baroreflex sensitivity. Additionally, transfection of adenoviral manganese superoxide dismutase also inhibited the augmentation of phosphorylated NFκB p65 in the nodose neurons from CHF rats. The present study suggests that superoxide-NFκB signaling contributes to CHF-induced baroreceptor dysfunction and resultant impairment of baroreflex function.
doi:10.1161/HYPERTENSIONAHA.113.02057
PMCID: PMC3893036  PMID: 24101667
baroreceptor; baroreflex; heart failure; NFκB; sodium channel; superoxide
3.  Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells 
BMC Neuroscience  2012;13:129.
Background
The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells.
Results
Whole-cell patch-clamp results showed that differentiation (9 days) didn’t change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential.
Conclusion
Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation.
doi:10.1186/1471-2202-13-129
PMCID: PMC3502467  PMID: 23095258
Action potential; Na+ channel; NG108-15 cell; Patch clamp; Single-cell real-time PCR; Western blot
4.  Mitochondria-Derived Superoxide Links to Tourniquet-Induced Apoptosis in Mouse Skeletal Muscle 
PLoS ONE  2012;7(8):e43410.
Our previous study has reported that superoxide mediates ischemia-reperfusion (IR)-induced necrosis in mouse skeletal muscle. However, it remains poorly understood whether IR induces apoptosis and what factors are involved in IR-induced apoptosis in skeletal muscle. Using a murine model of tourniquet-induced hindlimb IR, we investigated the relationship between mitochondrial dysfunction and apoptosis in skeletal muscle. Hindlimbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Compared to sham treatment, tourniquet-induced IR significantly elevated mitochondria-derived superoxide production, activated opening of mitochondrial permeability transition pore (mPTP), and caused apoptosis in the gastrocnemius muscles. Pretreatment with a superoxide dismutase mimetic (tempol, 50 mg/kg) or a mitochondrial antioxidant (co-enzyme Q10, 50 mg/kg) not only decreased mitochondria-derived superoxide production, but also inhibited mPTP opening and apoptosis in the IR gastrocnemius muscles. Additionally, an inhibitor of mPTP (cyclosporine A, 50 mg/kg) also inhibited both mPTP opening and apoptosis in the IR gastrocnemius muscles. These results suggest that mitochondria-derived superoxide overproduction triggers the mPTP opening and subsequently causes apoptosis in tourniquet-induced hindlimb IR.
doi:10.1371/journal.pone.0043410
PMCID: PMC3422247  PMID: 22912870

Results 1-4 (4)