Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts

Pierre, Sandrine V.; Yang, Changjun; Yuan, Zhaokan; Seminerio, Jennifer; Mouas, Christian; Garlid, Keith D.; Santos, Pierre Dos; Xie, Zijian

doi:10.1016/j.cardiores.2006.11.003

Cited by 62 publications

(76 citation statements)

References 47 publications

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“…PKCε-TIP inhibits activation of PKCε at the intracellular concentration of 3-10 nM and has been widely used to study the role of PKCε in cardiac function (26,31,41). A previous study has shown that 5 M of PKCε-TIP inhibits PKCε translocation in the heart of adult male rats in a Langendorff preparation (28). Consistent with the previous studies (4,28), the present study showed that PKCε-TIP had no significant effects on left ventricular function at the baseline levels.…”

Section: Discussionsupporting

confidence: 89%

“…Hearts were treated with 5 M PKCε-TIP before and during IPC. The dosage was chosen based on a previous study that showed 5 M of PKCε-TIP inhibited PKCε translocation in the heart of adult male rat in the Langendorff preparation (28). Treatment of the heart with PKCε-TIP did not significantly alter the baseline left ventricular function before ischemia (Table 1).…”

Section: Effect Of Pkc-tip On Ipcmentioning

confidence: 99%

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Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCε

Meyer¹,

Zhang²,

Zhang³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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natal cocaine exposure in rats resulted in decreased PKCε protein expression in the heart of adult male but not female offspring. The present study determined its functional consequence of inhibiting cardioprotection mediated by ischemic preconditioning. Pregnant Sprague-Dawley rats were administered intraperitoneally saline or cocaine (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) from day 15 to day 21 of gestational age. Hearts were isolated from 3-mo-old offspring and were subjected to ischemia and reperfusion injury in a Langendorff preparation, with or without prior ischemic preconditioning. Preischemic values of left ventricular function were the same between the saline control and cocaine-treated animals. Ischemic preconditioning of two episodes of 5-min ischemia significantly decreased infarct size and enhanced postischemic functional recovery of the left ventricle in the saline control animals. This ischemic preconditioning was associated with increased phospho-PKCε, but not phospho-PKC␦, levels and was blocked by a PKCε translocation inhibitor peptide. Prenatal cocaine treatment abolished the ischemic preconditioning-mediated increase in phospho-PKCε and cardioprotection in the heart of male offspring. In contrast, the cardioprotective effect was fully maintained in female offspring that were exposed to cocaine before birth. The results suggest that prenatal cocaine exposure causes a sex-specific loss of cardioprotection by ischemic preconditioning in adult offspring, which is most likely due to fetal programming of PKCε gene repression, resulting in a downregulation of PKCε function in the heart of adult male offspring.

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Section: Discussionsupporting

confidence: 89%

Section: Effect Of Pkc-tip On Ipcmentioning

confidence: 99%

Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCε

Meyer¹,

Zhang²,

Zhang³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…The findings presented here provide strong evidence that Na-K-ATPase ␣2 differs from ␣1 in its ability to act as a signal transducer, which carries several important implications. We and others have previously shown that activation of the sig- naling pool of Na-K-ATPase ␣1 by cardiotonic steroids is capable of protecting the heart from ischemic reperfusion injury (11,37,38,41). On the other hand, chronic stimulation of the Na-K-ATPase/Src receptor complex by either endogenous or infused cardiotonic steroids increases the generation of reactive oxygen species and induces cardiac hypertrophy and fibrosis in vivo (14,20,21,33,35).…”

Section: Discussionmentioning

confidence: 99%

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

Xie

Cui

et al. 2015

American Journal of Physiology-Cell Physiology

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Pase is a fundamental component of ion transport. Four ␣ isoforms of the Na-K-ATPase catalytic ␣ subunit are expressed in human cells. The ubiquitous Na-K-ATPase ␣1 was recently discovered to also mediate signal transduction through Src kinase. In contrast, ␣2 expression is limited to a few cell types including myocytes, where it is coupled to the Na ϩ /Ca 2ϩ exchanger. To test whether rat Na-KATPase ␣2 is capable of cellular signaling like its ␣1 counterpart in a recipient mammalian system, we used an ␣1 knockdown pig renal epithelial cell (PY-17) to create an ␣2-expressing cell line with no detectable level of ␣1 expression. These cells exhibited normal ouabain-sensitive ATPase, but failed to effectively regulate Src. In contrast to ␣1-expressing cells, ouabain did not stimulate Src kinase or downstream effectors such as ERK and Akt in ␣2 cells, although their signaling apparatus was intact as evidenced by EGF-mediated signal transduction. Additionally, ␣2 cells were unable to rescue caveolin-1. Unlike the NaKtide sequence derived from Na-K-ATPase ␣1, which downregulates basal Src activity, the corresponding ␣2 NaKtide was unable to inhibit Src in vitro. Finally, coimmunoprecipitation of cellular Src was diminished in ␣2 cells. These findings indicate that Na-K-ATPase ␣2 does not regulate Src and, therefore, may not serve the same role in signal transduction as ␣1. This further implies that the signaling mechanism of Na-K-ATPase is isoform specific, thereby supporting a model where ␣1 and ␣2 isoforms play distinct roles in mediating contraction and signaling in myocytes.rat Na-K-ATPase isoforms; Src tyrosine kinase; membrane transporters; ouabain; signal transduction THE NA-K-ATPASE, discovered in 1957 by Jens Skou, is a member of the P-type ATPase family and an integral membrane protein maintaining cellular ion homeostasis by pumping Na ϩ and K ϩ across the cell membrane (32). The protein consists of two noncovalently linked subunits, ␣ and ␤. The ␣-subunit contains the binding sites for substrates (e.g., ions and ATP) and ligands (e.g., ouabain) as it undergoes E1 and E2 conformational changes during a transport cycle. Four isoforms of the Na-K-ATPase ␣-subunit are expressed in humans. While ␣1 is expressed ubiquitously, ␣2 and ␣3 are primarily found in myocytes and neurons, respectively, and ␣4 is detected in sperm (3,4,31,45,50). Recent studies have revealed major differences in the physiological functions of each isoform. For example, the ␣2 isoform appears to possess the unique ability to regulate intracellular Ca 2ϩ levels in myocytes and coresides with the Na ϩ /Ca 2ϩ exchanger (5, 24). In addition, recent experiments using SWAP mice (ouabainsensitive ␣1 Na-K-ATPase mutant and ouabain-resistant ␣2 Na-K-ATPase mutant) suggest that the ␣2 isoform plays a more prominent role in calcium release in cardiac and smooth muscle myocytes than ␣1 (12).Over the last decade, we have also come to realize that the Na-K-ATPase may have many regulatory functions other than pumping ions across cell membranes. Studies fr...

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“…In addition to pumping Na ϩ and K ϩ across cell membranes, it also relays an extracellular ouabain signal to intracellular compartments via activation of different protein kinases (45). Pierre and coauthors (33) have provided evidence supporting the possibility that ouabain preconditioning may be cardioprotective in the therapeutic dose range. Ouabain preconditioning at concentrations without inotropic response before ischemia initiated a cardioprotective signaling pathway that induced ROS production and required mitoK ATP channel opening (32).…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Guo²,

Zhang³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic intermittent hypobaric hypoxia (CIHH) has been shown to attenuate intracellular Na+ accumulation and Ca2+ 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 Ca2+ 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 α1-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 α1-isoform by 76%, whereas the protein expression of the α2-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 α1-isoform of Na/K pump, which may be one of the mechanisms of CIHH against I/R-induced injury.

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Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts

Cited by 62 publications

References 47 publications

Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCε

Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCε

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

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

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