Na<sup>+</sup>/H<sup>+</sup> exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

Kusumoto, Keiji; Haist, James V.; Karmazyn, Morris

doi:10.1152/ajpheart.2001.280.2.h738

Cited by 124 publications

(101 citation statements)

References 32 publications

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“…Accordingly, inhibition of NHE by its specific inhibitor cariporide has been demonstrated to "rescue" several models of cardiac hypertrophy in vivo. [111][112][113] Because NHE inhibition does not appear to be associated with adverse hemodynamic consequences, this approach is a potentially interesting antihypertrophic treatment option.…”

Section: Na/h Exchangermentioning

confidence: 99%

Hypertrophy of the Heart

et al. 2004

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Abstract-Recent studies call into question the necessity of hypertrophic growth of the heart as a "compensatory" response to hemodynamic stress. These findings, coupled with recent progress in dissecting the molecular bases of hypertrophy, raise the prospect of suppressing hypertrophy without provoking circulatory insufficiency. In this article, we focus on signaling pathways that hold promise as potential targets for therapeutic intervention. We also summarize observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy. Key Words: hypertrophy Ⅲ heart failure Ⅲ signal transduction C ardiac hypertrophy is an adaptive response to pressure or volume stress, mutations of sarcomeric (or other) proteins, or loss of contractile mass from prior infarction. Hypertrophic growth accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease. In these types of cardiac pathology, pressure overload-induced concentric hypertrophy is believed to have a compensatory function by diminishing wall stress and oxygen consumption. 1-3 At the same time, ventricular hypertrophy is associated with significantly increased risk of heart failure and malignant arrhythmia. 4,5 In the 1960s, Meerson and colleagues 6 divided hypertrophic transformation of the heart into 3 stages: (1) developing hypertrophy, in which load exceeds output, (2) compensatory hypertrophy, in which the workload/mass ratio is normalized and resting cardiac output is maintained, and (3) overt heart failure, with ventricular dilation and progressive declines in cardiac output despite continuous activation of the hypertrophic program. The late-phase "remodeling" process that leads to failure is associated with functional perturbations of cellular Ca 2ϩ homeostasis 7 and ionic currents, 8,9 which contribute to an adverse prognosis by predisposing to ventricular dysfunction and malignant arrhythmia. Significant morphological changes include increased rates of apoptosis, 10 fibrosis, and chamber dilation. Even though the dichotomy between adaptive and maladaptive hypertrophy has been appreciated for more than a century, 11 mechanisms that determine how long-standing hypertrophy ultimately progresses to overt heart failure are poorly understood.At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in cell size, enhanced protein synthesis, and heightened organization of the sarcomere.Classically, 2 different hypertrophic phenotypes can be distinguished: (1) concentric hypertrophy due to pressure overload, which is characterized by parallel addition of sarcomeres and lateral growth of individual cardiomyocytes, and (2) eccentric hypertrophy due to volume overload or prior infarction, characterized by addition of sarcomeres in series and longitudinal cell growth. 12 At the molecular level, these changes in cellular phenotype are accompanied by reinduction of the so-called fetal gene program, because patterns of gene expression mimic those seen during ...

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Section: Na/h Exchangermentioning

confidence: 99%

Hypertrophy of the Heart

et al. 2004

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“…8,9 Activation of this exchanger in myocardial ischemia appears to be causally related to the calcium overload observed during ischemia, 10 and several studies have demonstrated protection from ischemic injury by NHE inhibition both in animal models of myocardial ischemia (MI) and in patients undergoing coronary interventions. [11][12][13] A protective effect of cariporide has recently been demonstrated in the setting of post-MI remodeling, 14 where protection could be demonstrated up to 3 months after MI.…”

Section: The Cardiac Namentioning

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

192

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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“…12,22 TGF␤ 1 binds to membrane receptors and transmits signals via mitogen-activated protein kinases (MAPK)-dependent and Smad-dependent pathways. 23 In postinfarcted myocardium, a condition in which NHE-1 inhibition proved to be beneficial, 3 Smad expression is elevated and normalized after Angiotensin II AT 1 blockade. 24,25 NHE-1 is a common downstream effector of various of these intracellular signaling mechanisms.…”

Section: Baseline and Cariporide-induced Changes In Sbp Lvw Lvw/bw mentioning

confidence: 99%

“…[2][3][4][5] The inhibition of NHE-1 reduces the hypertrophy of the surviving myocytes after myocardial infarction 3 and of the hearts of spontaneously hypertensive rats (SHR) 2 and mice overexpressing ␤ 1 -adrenergic receptors. 4 Taken together, these findings seem to indicate a key role of NHE activity in the development of myocardial hypertrophy.…”

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confidence: 99%

Regression of Hypertensive Myocardial Fibrosis by Na ⁺ /H ⁺ Exchange Inhibition

et al. 2003

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Abstract-We have recently reported that the inhibition of the Na ϩ /H ϩ exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SHR received 3.0 mg/kg per day of the specific NHE-1 inhibitor cariporide; the effect on cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis, and myocardial stiffness (length-tension relation in left papillary muscles) was evaluated at several time points (after 1, 2, or 3 months). A slight decrease of Ϸ5 mm Hg in systolic blood pressure was observed after 1 month of treatment with no further changes. After 2 and 3 months of treatment, the size of cardiomyocytes remained within normal values and myocardial fibrosis progressively decreased to normal level. Accordingly, myocardial stiffness and the serum levels of the carboxyterminal propeptide of procollagen type I, a marker of collagen type I synthesis, were normalized after 3 months. Left ventricular weight decreased from 910Ϯ43 (in untreated SHR) to 781Ϯ21 mg (treated SHR) after 3 months of treatment. No difference in body weight between treated and untreated SHR was observed after this period of treatment. The present data allow us to conclude that in the SHR the administration of an NHE-1 inhibitor for 2 or 3 months leads to the normalization of collagen type I synthesis, myocardial collagen volume fraction, and stiffness. Key Words: fibrosis Ⅲ myocardium Ⅲ extracellular matrix Ⅲ signal transduction F ibrous tissue accumulation is a feature of the structural remodeling of the myocardium seen in hypertensive heart disease. 1 An exaggerated accumulation of collagen type I and type III occurs in the hypertrophied myocardium and also in the nonhypertrophied right ventricle and in the atria of animals and humans with arterial hypertension. This collagen accumulation has adverse effects. It results in the development of increased myocardial stiffness that leads to diastolic dysfunction and ultimately to the development of systolic dysfunction.Recently, a new therapeutic strategy against hypertrophy has emerged from the use of Na ϩ /H ϩ exchanger (NHE) inhibitors. [2][3][4][5] The inhibition of NHE-1 reduces the hypertrophy of the surviving myocytes after myocardial infarction 3 and of the hearts of spontaneously hypertensive rats (SHR) 2 and mice overexpressing ␤ 1 -adrenergic receptors. 4 Taken together, these findings seem to indicate a key role of NHE activity in the development of myocardial hypertrophy. Even though our recent study showed that neither myocardial fibrosis nor stiffness was normalized in the SHR after 1 month of cariporide treatment, 2 the regression of fibrosis was observed after 6 months of NHE inhibition in another model of cardiac hypertrophy, the transgenic mice overexpressing ␤ 1 -adrenergic receptors. 4 Considering that the regression of myocyte hyp...

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Na⁺/H⁺ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

Cited by 124 publications

References 32 publications

Hypertrophy of the Heart

Hypertrophy of the Heart

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

Regression of Hypertensive Myocardial Fibrosis by Na ⁺ /H ⁺ Exchange Inhibition

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Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

Cited by 124 publications

References 32 publications

Hypertrophy of the Heart

Hypertrophy of the Heart

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

Regression of Hypertensive Myocardial Fibrosis by Na + /H + Exchange Inhibition

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Product

Resources

About

Na⁺/H⁺ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats

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

Regression of Hypertensive Myocardial Fibrosis by Na ⁺ /H ⁺ Exchange Inhibition