Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Abstract

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

Silencing of Sodium–Hydrogen Exchanger 1 Attenuates the Proliferation, Hypertrophy, and Migration of Pulmonary Artery Smooth Muscle Cells via E2F1

“…Studies also showed that the inhibition of NHE1 by inhibitors attenuated the hypertrophy of cardiomyocytes (23)(24)(25)(26)(27). Because we also found a significant decrease in the medial wall thickness of pulmonary arteries in NHE1-deficient mice with decreased hypoxic pulmonary hypertension and vascular remodeling (11), we hypothesized that the effects of NHE1 on hypoxia-induced PASMC hypertrophy were also mediated via E2F1.…”

“…Studies indicated the relationship between NHE1 and myocardial hypertrophy, showing that the inhibition of NHE1 activity by inhibitors reduced cardiac hypertrophy in animals and cultured cardiomyocytes (23)(24)(25)(26)(27). The increased medial wall thickness of pulmonary arteries in pulmonary hypertension and vascular remodeling is involved not only in the proliferation of PASMCs, but also in the hypertrophy of PASMCs.…”

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

“…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).…”

Early and Transient Sodium-Hydrogen Exchanger Isoform 1 Inhibition Attenuates Subsequent Cardiac Hypertrophy and Heart Failure Following Coronary Artery Ligation

“…The link between NHE-1 and calcineurin activation is reinforced by a number of previous studies linking the inhibition of NHE-1 activity with prevention of calcineurin activation (Ennis et al, 2007;Kili c et al, 2010;Guo et al, 2011). Moreover, myocardial NHE-1 overexpression in mice in the absence of insult results in hypertrophy and left ventricular dysfunction (Nakamura et al, 2008;Xue et al, 2010). Nakamura and colleagues (2008) have linked this phenomenon to calcineurin activation as a direct consequence of NHE-1-dependent elevation in intracellular Ca 21 concentrations.…”

“…A particularly important response to an elevation in intracellular calcium concentrations, and the subsequent formation of the calciumcalmodulin complex, is activation of calcineurin, a calciumactivated phosphatase critically important for the hypertrophic program (Frey and Olson, 2003). Indeed, overexpression of cardiac NHE-1 in transgenic mice on its own, in the absence of pathologic insult, has been shown to induce calcineurin upregulation and a calcineurin-dependent hypertrophic response (Nakamura et al, 2008;Xue et al, 2010;Mraiche et al, 2011).…”