Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

Abstract

Background— Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na + /H + exchanger NHE-1 to cardiac remodeling in GC-A–deficient (GC-A −/− ) mice. Methods and Results— Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A −/− mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca 2+ levels. Chronic treatment of GC-A −/− mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca 2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A −/− mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca 2+ /calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A −/− mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy. Conclusions— On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca 2+ , and CaMKII as well as Akt activity.

Na+/H+ Exchanger 1 Directly Binds to Calcineurin A and Activates Downstream NFAT Signaling, Leading to Cardiomyocyte Hypertrophy

“…Recently, we demonstrated that transgenic expression of an activated form of NHE1 causes cardiac hypertrophy and heart failure due to activation of Ca 2ϩ -dependent prohypertrophic factors (e.g., CaN and Ca 2ϩ /CaM-dependent protein kinase II) via increased cytosolic [Ca 2ϩ ] and [Na ϩ ] (37). Indeed, there are many reports demonstrating that the expression level of NHE1 is elevated in various hypertrophic animal models (12,23,24). In the present study, we demonstrated that overexpression of NHE1 resulted in cardiomyocyte enlargement and augmented hypertrophic gene (ANF and RCAN1) expression.…”

“…Activation of NHE1 is also involved in cardiac hypertrophy and heart failure, as shown by studies in animal models and isolated cardiomyocytes (10,12,21,37,53). The expression level of NHE1 was reported to be elevated in various hypertrophic animal models (12,24). Furthermore, we recently reported that, based on results using transgenic mice with activated NHE1, activation of NHE1 is sufficient for increasing prohypertrophic Ca 2ϩ signals, leading to cardiac hypertrophy and heart failure (37).…”

Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart

“…39 Other molecules downstream of PKG also merit consideration for a role in the antihypertrophic action of natriuretic peptide/GC-A signal transduction. Recently, Kilic et al 40 reported that GC-A moderates cardiac growth response to pressure overload by preventing excessive activation of the Na ϩ /H ϩ exchanger NHE-1 and subsequent increases in Ca 2ϩ / calmodulin-dependent kinase II as well as Akt. This demon- Mechanism of GC-A-mediated inhibition of cardiac hypertrophy suggested from the findings of this and previous studies.…”

Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy

“…82 Recently, a very interesting study reported that cardiac hypertrophy of atrial natriuretic peptide receptor-deficient mice was accompanied by an increased activity of NHE-1 with increased [Ca 2ϩ ] i . 83 Long-term treatment with the NHE-1 inhibitor cariporide normalized these alterations. 80 These results are in line with a report by Tajima et al, who demonstrated that atrial natriuretic peptide inhibits NHE-1 activity.…”

“…Interestingly, whereas long-term NHE-1 inhibition by cariporide in the whole animal induces upregulation of the exchanger, 103 the normalization of its previously augmented expression has also been reported after long-term NHE-1 inhibition. 74,75,83,89 Several aspects require further investigation to clarify the precise mechanism by which NHE-1 is involved in the development of cardiac hypertrophy and failure and its possible link with other intracellular signaling pathways. A disparate negative result about the antihypertrophic effect of NHE-1 inhibition in rats was reported by Loennechen et al, 104 who described a salutary effect of losartan on postinfarction remodeling and gene expression that was not shared by cariporide.…”