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            Regulation in Myocardium of the Spontaneously Hypertensive Rat

Pérez, Néstor Gustavo; Álvarez, Bernardo V.; Hurtado, María C. Camilión de; Cingolani, Horacio E.

doi:10.1161/01.res.77.6.1192

Cited by 102 publications

(57 citation statements)

References 47 publications

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“…In this regard, Iso-induced CH seems to differ from other models of CH in which enhanced NHE-1 activity 17,18 is not correlated with an increase in expression of the antiporter, 17,19 suggesting a role for posttranslational mechanisms. Iso-induced effects are attenuated by chronic inhibition of the exchanger.…”

Section: Discussionmentioning

confidence: 67%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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Abstract-Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either ␣-or ␤-adrenergic stimulation. Because an association between the Na ϩ /H ϩ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na ϩ /H ϩ exchanger activity (3 mg · kg) was given to male Wistar rats for 30 days. Sex-and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenolϩBIIB723-treated group. Heart weight-to-body weight ratio at necropsy was 2.44Ϯ0.11 in controls and increased to 3.35Ϯ0.10 (PϽ0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82Ϯ0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na ϩ /H ϩ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45Ϯ0.11 vs 0.91Ϯ0.05 arbitrary units, PϽ0.05). This effect was significantly reduced by BIIB723 (1.17Ϯ0.02, PϽ0.05). In conclusion, our results show that Na ϩ /H ϩ exchanger inhibition prevented the development of isoproterenolinduced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy. Key Words: hypertrophy, cardiac Ⅲ signal transduction Ⅲ antiporters Ⅲ fibrosis Ⅲ adrenergic receptor agonists I ncreased sympathetic activity is often implicated in the development of cardiac hypertrophy (CH). A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, 5-7 the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1). This study provides evidence indicating a key role for NHE-1 activity as a mechanism underlying the development of CH and fibrosis induced by I...

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Section: Discussionmentioning

confidence: 67%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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“…Interestingly, we have found alterations in intracellular calcium handling in ␤ 1 -adrenergic receptor transgenic mice that are similar to human heart failure and include markedly prolonged calcium transients. 15 Furthermore, increased NHE1 activity has been demonstrated in the myocardium of spontaneously hypertensive rats 21,22 and after treatment of cardiac myocytes with hypertrophic agonists of Gq-coupled pathways such as endothelin, 23 angiotensin, 24 and thrombin. 25 Takewaki et al 26 showed in cultured myocytes that NHE inhibition partially inhibited stretch-induced activation of MAP-kinases and activation of MAP-kinases was linked to hypertrophic signaling of adrenergic receptors.…”

Section: Engelhardt Et Al Nhe Inhibition In ␤ 1 -Receptor Transgenic mentioning

confidence: 99%

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

Engelhardt

Hein

Keller

et al. 2002

Circulation Research

193

102

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Abstract-Chronic stimulation of the ␤ 1 -adrenergic receptor leads to hypertrophy and heart failure in ␤ 1 -adrenergic receptor transgenic mice and contributes to disease progression in heart failure patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified the cardiac Na ϩ -H ϩ exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. ␤ 1 -Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (ϩ140Ϯ6%) and protein (ϩ42Ϯ19%). In order to test whether increased NHE1 is causally related to ␤ 1 -adrenergic-induced hypertrophy, fibrosis, and heart failure, ␤ 1 -adrenergic receptor transgenic (TG) and wild-type (WT) littermates were treated with a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control chow for 8 months. There was significant hypertrophy of cardiac myocytes in ␤ 1 -adrenergic receptor transgenic mice (2.3-fold increase in myocyte cross-sectional area), which was virtually absent in cariporide-fed animals. Interstitial fibrosis was prominent throughout the left ventricular wall in nontreated ␤ 1 -adrenergic receptor transgenic mice (4.8-fold increase in collagen volume fraction); cariporide treatment completely prevented this development of fibrosis. Left ventricular catheterization showed that cariporide also prevented the loss of contractile function in ␤ 1 -adrenergic receptor transgenic mice: whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250Ϯ570 mm Hg/s TG versus 7360Ϯ540 mm Hg/s WT, dp/dt max ), this decrease was completely prevented by cariporide (8150Ϯ520 mm Hg/s TG cariporide). Inhibition of NHE1 prevented the development of heart failure in ␤ 1 -receptor transgenic mice. We conclude that the cardiac Na ϩ -H ϩ exchanger 1 is essential for the detrimental cardiac effects of chronic ␤ 1 -receptor stimulation in the heart. (Circ Res. 2002;90:814-819.)

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“…Enhanced activity of the NHE1 was first reported in the hypertrophic myocardium of spontaneously hypertensive rats by Perez et al (47). Thereafter, NHE1 protein expression and activity have been demonstrated to be elevated in a variety of cardiovascular diseases, including in hypertensive, hypertrophied, and diabetic myocardium (7,18,30,32), in hearts subjected to ischemia (24), in isolated cardiomyocytes subjected to chronic acidosis (16), and in patients with end-stage heart failure (55).…”

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confidence: 99%

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

Xue¹,

Mraiche

Zhou³

et al. 2010

Physiological Genomics

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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.

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pH _i Regulation in Myocardium of the Spontaneously Hypertensive Rat

Cited by 102 publications

References 47 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

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

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

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pH i Regulation in Myocardium of the Spontaneously Hypertensive Rat

Cited by 102 publications

References 47 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

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

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

Contact Info

Product

Resources

About

pH _i Regulation in Myocardium of the Spontaneously Hypertensive Rat

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

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

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