Improved Myocardial Function Using a Na+/H+ Exchanger Inhibitor During Cardioplegic Arrest and Cardiopulmonary Bypass

Cox, Charles S.; Allen, Steven J.; Sauer, Henning; Laine, Glen A.

doi:10.1378/chest.123.1.187

Cited by 11 publications

(5 citation statements)

References 24 publications

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“…NHE1 is a key component of the heart's response to intracellular acidosis following ischemic insult. NHE1 activation during reperfusion is clearly detrimental to the heart, and the inhibition of this exchanger before reperfusion could reduce the associated myocardial damage (Cox et al, 2003;Garciarena et al, 2008). Our data showed that the expression of NHE1 protein was dramatically decreased in cardiac ischemia (Supplementary Figure S15).…”

Section: Discussionmentioning

confidence: 67%

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Xu¹,

Pan²,

Li³

et al. 2015

J Mol Cell Biol

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The mammalian nuclear pore complex is comprised of ∼ 30 different nucleoporins (Nups). It governs the nuclear import of gene expression modulators and the export of mRNAs. In cardiomyocytes, Na(+)-H(+) exchanger-1 (NHE1) is an integral membrane protein that exclusively regulates intracellular pH (pHi) by exchanging one intracellular H(+) for one extracellular Na(+). However, the role of Nups in cardiac NHE1 expression remains unknown. We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA. The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. Nup35 ablation weakens the resistance of cardiomyocytes to an acid challenge by depressing NHE1 expression. Moreover, we identify that Nup35 and NHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro. Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification. We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression. This finding reveals a novel regulatory mechanism of cardiomyocyte pHi, and may provide insight into the therapeutic strategy for ischemic cardiac diseases.

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Section: Discussionmentioning

confidence: 67%

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Xu¹,

Pan²,

Li³

et al. 2015

J Mol Cell Biol

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“…In clinical situations, tissue edema in the periinfarct zone is usually related to reversible ischemic injury. It has been well demonstrated that the dysfunction of the ion pumps and channels on the cell membranes is the principal mechanism of the ischemia‐associated myocardial edema (28–30). Water accumulation in the intracellular compartment seems to be a key component of ischemia‐induced edema.…”

Section: Discussionmentioning

confidence: 99%

Tissue edema does not change gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA)‐enhanced T₁ relaxation times of viable myocardium

Xiang

Dai

et al. 2005

Magnetic Resonance Imaging

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Purpose:To determine whether tissue edema changes gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced T 1 relaxation times of the viable myocardium. Materials and Methods:A total of 16 isolated pig hearts were divided into four groups (N ϭ 4/group) and perfused in a Langendorff apparatus. Gd-DTPA was injected into the aortic perfusion line. Tissue edema was then induced by two hours of simultaneous arterial/venous perfusion (SAVP). Myocardial water content and T 1 relaxation times were monitored throughout SAVP. The volumes of the extracellular and intracellular compartments were assessed using 31 P MRS-detectable markers, phenylphosphonic acid (PPA) and dimethyl methylphosphonate (DMMP).Results: Tissue water content in both viable and infarcted myocardium increased significantly during two-hour SAVP. However, Gd-DTPA-enhanced T 1 relaxation times of the viable myocardium remained relatively unchanged. Infarcted myocardium, on the other hand, exhibited significant T 1 shortening during SAVP. Furthermore, SAVP resulted in significant expansions of both extracellular and intracellular compartments, but the ratio of the volumes of the two compartments remained relatively constant. Conclusion:Tissue edema in the viable myocardium does not increase the relative distribution volume of the contrast agent. As a result, edema does not change Gd-DTPA-enhanced T 1 relaxation times of the viable myocardium.

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“…These data suggest that Na ϩ accumulation by the cardiac myocyte likely initiated a cellular signaling cascade that perhaps includes increased myocyte inflammation, as indicated by increased myocyte secretion of TNF-␣, IL-1␤, and IL-6, culminating in myocardial contractile depression. Pharmacological interventions that limit the rise in intracellular Na ϩ have been shown to reduce myocardial injury and improve myocardial performance in several experimental models (12,26,37,43). Since the Na-K-ATPase exchanger is the primary regulator of sodium efflux from the cell, a pharmacological agent that increases Na-K-ATPase activity should promote Na ϩ efflux from the cell, limit injury-related Na ϩ accumulation, and provide organ protection (13).…”

Section: Discussionmentioning

confidence: 99%

Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition

Horton

Tan²,

White³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Improved Myocardial Function Using a Na+/H+ Exchanger Inhibitor During Cardioplegic Arrest and Cardiopulmonary Bypass

Cited by 11 publications

References 24 publications

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Tissue edema does not change gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA)‐enhanced T₁ relaxation times of viable myocardium

Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition

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Improved Myocardial Function Using a Na+/H+ Exchanger Inhibitor During Cardioplegic Arrest and Cardiopulmonary Bypass

Cited by 11 publications

References 24 publications

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na+-H+exchanger-1 expression

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na+-H+exchanger-1 expression

Tissue edema does not change gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA)‐enhanced T1 relaxation times of viable myocardium

Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition

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Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na⁺-H⁺exchanger-1 expression

Tissue edema does not change gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA)‐enhanced T₁ relaxation times of viable myocardium