Na⁺/H⁺ exchange inhibition attenuates left ventricular remodeling and preserves systolic function in pressure‐overloaded hearts

Abstract

1 Cardiac hypertrophy is a homeostatic response to elevated afterload. Na þ /H þ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na þ /H þ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. 2 Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. 3 After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about þ 50%) and normal chamber size and function, whereas cariporidetreated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. 4 In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition. British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631 Keywords: Pressure overload; Na þ /H þ exchanger; cardiac remodeling; systolic function Abbreviations: BW, body weight; Car, cariporide; Car-Bd, cariporide-treated, banded mice; Car-Sh, cariporide-treated, shamoperated mice; CSA, cardiomyocyte cross-sectional area; Ees, end-systolic elastance; HR, heart rate; LVEDD, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LV FS, left ventricular fractional shortening; LVSP, left ventricular systolic pressure; LVW/BW, left ventricular weight-to-body weight ratio; NHE-1, Na þ /H þ exchanger isoform 1; RWT, posterior-wall thickness-to-left ventricular end-diastolic diameter ratio; s s , end-systolic left ventricular wall stress; Veh-Sh, vehicle-treated, sham-operated mice; Veh-Bd, vehicle-treated, banded mice

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

“…A variety of stimuli can lead to cardiac hypertrophy, including elevated arterial blood pressure, myocardial infarction, valvular heart disease, and cardiomyopathy (23). NHE1 inhibition has been proven to prevent or induce regression of hypertrophy in several models of cardiac hypertrophy (6,7,18,19,32,35,40). However, it is still largely unknown by what mechanism(s) elevated NHE1 propagates hypertrophic injury, although a number of pathways have been proposed (20,44).…”

“…Hearts were fixed in 10% buffered formalin overnight, embedded in paraffin, and serially sectioned into 5-m slices (6,40). Samples were stained with hematoxylin and eosin (H & E) to evaluate gross morphology and cross-sectional area (CSA) or with picrosirius red to assess fibrosis (41).…”

“…Dimensions of at least 100 cells from 3 or 4 sections per heart were measured. Visual fields were accepted for quantification if nuclei were visible and cell membranes were intact (40,41). Interstitial fibrosis (IF) was measured from digitized images with Openlab 3.5 (Improvision, Waltham, MA).…”

Regulation and Role of the Presynaptic and Myocardial Na+/H+ Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

“…An increase of myocardial NHE1 mRNA, protein, and/or activity has been documented in response to pressure and volume overload (Baartscheer et al 2003;Marano et al 2004), hypertension (Camilion de Hurtado et al 2002;Cingolani et al 2003), ischemia, and reperfusion (for review, see Avkiran 1999;, myocardial infarction (Chen et al 2004), rapid left ventricular pacing (Aker et al 2004;Leineweber et al 2006), idiopathic dilated cardiomyopathy (Taniguchi et al 1996) and chronic end-stage heart failure (Yokoyama et al 2000).…”

Antihypertrophic Effect of Na+/H+Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

“…Studies using different models of cardiac remodeling and heart failure demonstrated that NHE-1 inhibition improves heart performance, particularly ventricular dysfunction and hypertrophy (Yoshida and Karmazyn, 2000;Kusumoto et al, 2001;Cingolani et al, 2003;Marano et al, 2004). NHE-1 inhibitors have been shown to reduce the hypertrophic response to various extracellular stimuli in cul-tured cardiac cells (Hori et al, 1990;Yamazaki et al, 1998;Karmazyn et al, 2003).…”