Circulation Research. 2002
Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014966.97486.C0
Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014966.97486.C0
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Submitted on September 27, 2001
Revised on February 26, 2002
Accepted on February 27, 2002
Inhibition of Na+-H+ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in ß1-Adrenergic Receptor Transgenic Mice
Stefan Engelhardt ;
From the Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
* To whom correspondence should be addressed. E-mail: lohse{at}toxi.uni-wuerzburg.de.
Chronic stimulation of the ß1-adrenergic receptor leads to hypertrophy and heart failure in ß1-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+-H+ exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. ß1-Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (+140±6%) and protein (+42±19%). In order to test whether increased NHE1 is causally related to ß1-adrenergic--induced hypertrophy, fibrosis, and heart failure, ß1-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 ß1-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 ß1-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 ß1-adrenergic receptor transgenic mice, whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250±570 mm Hg/s TG versus 7360±540 mm Hg/s WT, dp/dtmax) this decrease was completely prevented by cariporide (8150±520 mm Hg/s TG cariporide). Inhibition of NHE1 prevented the development of heart failure in ß1-receptor transgenic mice. We conclude that the cardiac Na+-H+ exchanger 1 is essential for the detrimental cardiac effects of chronic ß1-receptor stimulation in the heart.
Key words: transgenic mouse • heart failure • ß-adrenergic receptor • Na+-H+ exchanger • cariporide
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