Inhibition of Na
 +
 -H
 +
 Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β
 1
 -Adrenergic Receptor Transgenic Mice

Engelhardt, Stefan; Hein, Lutz; Keller, U.; Klämbt, Kerstin; Lohse, Martin J.

doi:10.1161/01.res.0000014966.97486.c0

Cited by 193 publications

(124 citation statements)

References 41 publications

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“…However, recent studies have shown that longer-term treatment with NHE1 inhibitors might protect against cardiac hypertrophy and heart failure. 47,48 One concern about longterm therapy using these inhibitors is the possibility that compensation might occur that would lessen the therapeutic benefits. The apparent upregulation of NHE1 in response to treatment of normal rats with NHE inhibitors raises the possibility that cardiac injury might be enhanced if myocardial infarction were to occur just after the inhibitor was withdrawn.…”

Section: Discussionmentioning

confidence: 99%

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Wang

Meyer

Ashraf

et al. 2003

Circulation Research

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Abstract-Pharmacological studies indicate that Naϩ -H ϩ exchanger isoform 1 (NHE1) plays a central role in myocardial ischemia-reperfusion injury; however, confirmation by alternative methods is lacking. To address this issue, we examined the role of NHE1 in ischemia-reperfusion injury using gene-targeted NHE1-null mutant (Nhe1 Ϫ/Ϫ ) mice. Nhe1Ϫ/Ϫ and wild-type hearts were perfused in a Langendorff apparatus in both the absence and presence of the NHE1 inhibitor eniporide, subjected to 40 minutes of ischemia and 30 minutes of reperfusion, and the effects of genetic ablation or inhibition of NHE1 on hemodynamic, biochemical, and pathological changes were assessed. In the absence of eniporide, left ventricular developed pressure, end-diastolic pressure, and coronary flow were significantly less impaired in Nhe1 Ϫ/Ϫ hearts relative to wild-type hearts, and release of lactate dehydrogenase, morphological damage, and ATP depletion were also significantly less. In the presence of eniporide, however, wild-type hearts were significantly protected and there were no significant differences between the two genotypes with respect to cardiac performance, lactate dehydrogenase release, or morphological damage. Furthermore, the presence or absence of eniporide had no apparent effect on the degree of cardioprotection observed in Nhe1 Ϫ/Ϫ hearts. These data demonstrate that genetic ablation of NHE1 protects the heart against ischemia-reperfusion injury. In addition to providing direct evidence that confirms previous pharmacological studies indicating a role for NHE1 in ischemia-reperfusion injury, these results suggest that the long-term absence of NHE1 does not elicit major compensatory changes that might negate the cardioprotective effects of blocking its activity over the short-term.

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Section: Discussionmentioning

confidence: 99%

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Wang

Meyer

Ashraf

et al. 2003

Circulation Research

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“…136 However, in ␤ 1 -receptor transgenic mice NHE1 is upregulated, and pharmacological NHE1 inhibition prevented the development of hypertrophy, fibrosis, and heart failure. 137 The mechanisms of the protective effects of NHE1 inhibition, the roles of intracellular sodium and calcium, and NHE1 regulation remain to be investigated. 137,138 Apoptosis ␤-Receptor stimulation causes apoptosis of isolated rat cardiomyocytes.…”

Section: Sodium Proton Exchanger Nhe1mentioning

confidence: 99%

“…137 The mechanisms of the protective effects of NHE1 inhibition, the roles of intracellular sodium and calcium, and NHE1 regulation remain to be investigated. 137,138 Apoptosis ␤-Receptor stimulation causes apoptosis of isolated rat cardiomyocytes. Different approaches demonstrate proapoptotic effects of ␤ 1 and antiapoptotic effects of ␤ 2 -receptors.…”

Section: Sodium Proton Exchanger Nhe1mentioning

confidence: 99%

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Lohse

Engelhardt²,

Eschenhagen³

2003

Circulation Research

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583

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Abstract-This review addresses open questions about the role of ␤-adrenergic receptors in cardiac function and failure.Cardiomyocytes express all three ␤-adrenergic receptor subtypes-␤ 1 , ␤ 2 , and, at least in some species, ␤ 3 . The ␤ 1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The ␤ 2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the ␤ 1 subtype. In heart failure, the sympathetic system is activated, cardiac ␤-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, ␤-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the ␤-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.

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“…Quantification of left ventricular fibrosis was achieved by Sirius red staining followed by semiautomated image analysis, as described. 6 …”

Section: Morphological Analysismentioning

confidence: 99%

Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation

et al. 2004

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Background-Chronic adrenergic stimulation leads to cardiac hypertrophy and heart failure in experimental models and contributes to the progression of heart failure in humans. The pathways mediating the detrimental effects of chronic ␤-adrenergic stimulation are only partly understood. We investigated whether genetic modification of calcium handling through deletion of phospholamban in mice would affect the development of heart failure in mice with transgenic overexpression of the ␤ 1 -adrenergic receptor. Methods and Results-We crossed ␤ 1 -adrenergic receptor transgenic (␤ 1 TG) mice with mice homozygous for a targeted deletion of the phospholamban gene (PLB Ϫ/Ϫ ). Phospholamban ablation dramatically enhanced survival of ␤ 1 TG mice. The decrease of left ventricular contractility typically observed in ␤ 1 TG mice was reverted back to normal by phospholamban ablation. Cardiac hypertrophy and fibrosis were significantly inhibited in ␤ 1 TG/PLB Ϫ/Ϫ mice compared with ␤ 1 TG mice, and the heart failure-specific gene expression pattern was normalized. Analysis of intracellular calcium transients revealed increased diastolic calcium levels and decreased rate constants of diastolic calcium decline in ␤ 1 TG mice. In ␤ 1 TG/PLB Ϫ/Ϫ mice, diastolic calcium concentration was normal and rate constants of diastolic calcium decline were greater than in wild-type mice. Conclusions-We conclude that modification of abnormal calcium handling in ␤ 1 TG mice through ablation of phospholamban resulted in a rescue of functional, morphological, and molecular characteristics of heart failure in ␤ 1 -adrenergic receptor-transgenic mice. These results imply altered calcium handling as critical for the detrimental effects of ␤ 1 -adrenergic signaling.

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Inhibition of Na ⁺ -H ⁺ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β ₁ -Adrenergic Receptor Transgenic Mice

Cited by 193 publications

References 41 publications

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation

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Inhibition of Na + -H + Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β 1 -Adrenergic Receptor Transgenic Mice

Cited by 193 publications

References 41 publications

Mice With a Null Mutation in the NHE1 Na + -H + Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Mice With a Null Mutation in the NHE1 Na + -H + Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation

Contact Info

Product

Resources

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Inhibition of Na ⁺ -H ⁺ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β ₁ -Adrenergic Receptor Transgenic Mice

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury