Yong-Li Wang

Na+-K+-ATPase, a potent neuroprotective modulator against Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na+‐K+‐ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in‐depth understanding of Na+‐K+‐ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD.

Chronic intermittent hypobaric hypoxia protects the heart against ischemia/reperfusion injury through upregulation of antioxidant enzymes in adult guinea pigs

AbstractAim:To investigate the protection and the anti-oxidative mechanism afforded by chronic intermittent hypobaric hypoxia (CIHH) against ischemia/reperfusion (I/R) injury in guinea pig hearts.Methods:Adult male guinea pigs were exposed to CIHH by mimicking a 5000 m high altitude (pB=404 mmHg, pO2=84 mmHg) in a hypobaric chamber for 6 h/day for 28 days. Langendorff-perfused isolated guinea pig hearts were used to measure variables of left ventricular function during baseline perfusion, ischemia and the reperfusion period. The activity and protein expression of antioxidant enzymes in the left myocardium were evaluated using biochemical methods and Western blotting, respectively. Intracellular reactive oxygen species (ROS) were assessed using ROS-sensitive fluorescence.Results:After 30 min of global no-flow ischemia followed by 60 min of reperfusion, myocardial function had better recovery rates in CIHH guinea pig hearts than in control hearts. The activity and protein expression of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of CIHH guinea pigs. Pretreatment of control hearts with an antioxidant mixture containing SOD and CAT exerted cardioprotective effects similar to CIHH. The irreversible CAT inhibitor aminotriazole (ATZ) abolished the cardioprotection of CIHH. Cardiac contractile dysfunction and oxidative stress induced by exogenous hydrogen peroxide (H2O2) were attenuated by CIHH and CAT.Conclusions:These data suggest that CIHH protects the heart against I/R injury through upregulation of antioxidant enzymes in guinea pig.

Sesamin ameliorates doxorubicin-induced cardiotoxicity: Involvement of Sirt1 and Mn-SOD pathway

Oxidative stress caused by doxorubicin (DOX) is believed to be a major underlying molecular mechanism of DOX-induced cardiotoxicity. Sesamin (Ses), an active component extracted from sesame seeds, exhibits antioxidative and anti-inflammatory effects. In the present study, possible protective mechanisms of Ses on DOX-induced cardiotoxicity were investigated in rats and cultured H9C2 cells. We demonstrated that Ses exhibits a significant protective effect on cardiac tissue in animal and cell models of DOX-induced cardiac injury. Moreover, Ses can ameliorate DOX-induced oxidative stress and mitochondrial damage. Further studies suggested that Ses is able to up-regulate the protein expression of Mn-SOD in normal rats and to restore the decreased expression of Mn-SOD in DOX-induced cardiac injury rats. Exposure to Ses or DOX alone slightly increased the protein expression of Sirt1; however, a more remarkable increase in Sirt1 protein level was detected in the Ses+DOX group. Treatment with a pan-sirtuin inhibitor (nicotinamide) or a Sirt1-specific inhibitor (EX-527) partially antagonised the effect of Ses on DOX-induced mitochondrial damage and completely abolished the effect of Ses on Mn-SOD expression. These findings indicate that the protective mechanisms of Ses on DOX-induced cardiotoxicity are involved in the alleviation of oxidative stress injury and Mn-SOD dysfunction, partially via the activation of Sirt1.

Enhancement of Na/K pump activity by chronic intermittent hypobaric hypoxia protected against reperfusion injury

Chronic intermittent hypobaric hypoxia (CIHH) has been shown to attenuate intracellular Na(+) accumulation and Ca(2+) overload during ischemia and reperfusion (I/R), both of which are closely related to the outcome of myocardial damage. Na/K pump plays an essential role in maintaining the equilibrium of intracellular Na(+) and Ca(2+) during I/R. It has been shown that enhancement of Na/K pump activity by ischemic preconditioning may be involved in the cardiac protection. Therefore, we tested whether Na/K pump was involved in the cardioprotection by CIHH. We found that Na/K pump current in cardiac myocytes of guinea pigs exposed to CIHH increased 1.45-fold. The K(1) and f(1), which reflect the portion of α(1)-isoform of Na/K pump, dramatically decreased or increased, respectively, in CIHH myocytes. Western blot analysis revealed that CIHH increased the protein expression of the α(1)-isoform by 76%, whereas the protein expression of the α(2)-isoform was not changed significantly. Na/K pump current was significantly suppressed in simulated I/R, and CIHH preserved the Na/K pump current. CIHH significantly improved the recovery of cell length and contraction during reperfusion. Furthermore, inhibition of Na/K pump by ouabain attenuated the protective effect afforded by CIHH. Collectively, these data suggest that the increase of Na/K pump activity following CIHH is due to the upregulating α(1)-isoform of Na/K pump, which may be one of the mechanisms of CIHH against I/R-induced injury.

Na+/K+‐ATPase inhibition upregulates NMDA‐evoked currents in rat hippocampal CA1 pyramidal neurons

Na+/K+‐ATPase and N‐methyl‐d‐aspartate (NMDA) receptor in hippocampus play very important roles in the regulation of learning and memory. Here, we showed that dihydroouabain (DHO, 10−5–10−3 m), a Na+/K+‐ATPase inhibitor, significantly potentiated NMDA current in rat hippocampal CA1 pyramidal neurons, which was blocked by PP2 (the selective Src tyrosine kinase inhibitor) and PD‐98059 [the selective inhibitor of the mitogen‐activated protein kinases (MAPK) cascade]. These findings reported here uncover that Src mediates the cross‐talk between Na+/K+‐ATPase and NMDA receptor to transduce the signals from Na+/K+‐ATPase to the MAPK cascade and provide new insights into therapeutic target for deeper understanding of the nature of cognitive disorder.

Isoform-specific regulation of the Na+-K+ pump by adenosine in guinea pig ventricular myocytes

AbstractAim:The present study investigated the effect of adenosine on Na+-K+ pumps in acutely isolated guinea pig (Cavia sp.) ventricular myocytes.Methods:The whole-cell, patch-clamp technique was used to record the Na+-K+ pump current (Ip) in acutely isolated guinea pig ventricular myocytes.Results:Adenosine inhibited the high DHO-affinity pump current (Ih) in a concentration-dependent manner, which was blocked by the selective adenosine A1 receptor antagonist DPCPX and the general protein kinase C (PKC) antagonists staurosporine, GF 109203X or the specific δ isoform antagonist rottlerin. In addition, the inhibitory action of adenosine was mimicked by a selective A1 receptor agonist CCPA and a specific activator peptide of PKC-δ, PP114. In contrast, the selective A2A receptor agonist CGS21680 and A3 receptor agonist Cl-IB-MECA did not affect Ih. Application of the selective A2A receptor antagonist SCH58261 and A3 receptor antagonist MRS1191 also failed to block the effect of adenosine. Furthermore, H89, a selective protein kinase A (PKA) antagonist, did not exert any effect on adenosine-induced Ih inhibition.Conclusion:The present study provides the electrophysiological evidence that adenosine can induce significant inhibition of Ih via adenosine A1 receptors and the PKC-δ isoform.

Different Na + /K + -ATPase signal pathways was involved in the increase of (Ca 2+ ) i induced by strophanthidin in normal and failing isolated guinea pig ventricular myocytes

AbstractAim:To determine whether different Na+/K+ -ATPase signal transduction pathways have positive inotropic effects on normal ventricular myocytes (NC) and failing ventricular myocytes (FC), and are involved in an increase of [Ca2+]i induced by strophanthidin (Str).Methods:A guinea pig model of congestive heart failure was made by constricting descending aorta. The left ventricular myocytes were enzymatically isolated. The effects of 25 μmol/L Str with different signal-transducing inhibitors on contractility and the calcium transient of NC or FC from guinea pigs were simultaneously assessed and compared with those in the 25 μmol/L Stronly group by a video-based, motion-edge detection system.Results:Str at 1, 10, and 25 μmol/L in NC and Str at 0.1, 1, 10, and 25 μmol/L) in FC elevated the calcium transient amplitude and increased the positive inotropic effects in a concentration-dependent manner, respectively. At the same concentration, the effects of Str were more potent in FC than in NC. In FC, both the mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) signal transduction pathway of Na+/K+-ATPase were involved in the increase of the calcium transient induced by Str, but only activation of the MAPK pathway increased the calcium transient in NC. However, only the ROS pathway was involved in positive inotropic effects both in NC and FC.Conclusion:The present study suggests that Na+/K+-ATPase signaling pathways involved in the inotropic effects of Str in NC and FC are consistent, and Na+/K+-ATPase signaling pathways involved in the increase of [Ca2+]i by Str in NC and FC are different.