Role of AE3 and NHE1 in cardiomyocyte homeostasis and remodeling

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Stimulation of Na+/H+-exchange in cardiomyocytes is a common feature in cardiac pathology. Remarkably, activation of the Na+/H+-exchanger NHE1 does not necessarily entail a fall of pHi, because it can be balanced by induction of the anion-exchanger AE3. This simultaneous activation is thought to raise intracellular Na+ concentration and hence inhibit Na+/Ca2+-exchange. The concomitant intracellular Ca2+ accumulation may then promote cardiac hypertrophy. Indeed, NHE1 inhibitors had a positive effect on cardiac remodeling in diverse animal studies. Because of the functional interplay between NHE1 and AE3, we address the role of AE3 in the intact and the diseased heart. We have generated constitutive AE3-knockout mice, which revealed a significant reduction of the heart to body weight ratio. We now established a floxed Ae3-mouse that will allow us to disrupt AE3 specifically in the heart. In vivo characterization of this mouse will include electrocardiograms, blood pressure and echocardiography. In vitro analysis will cover heart weights, histology, intracellular Na+ concentration, cardiomyocyte contractility, regulation of pHi and Ca2+ transients. Because of the suggested role of AE3 we will subsequently assess cardiac remodeling models in the absence of AE3. In parallel, we will overexpress AE3 and/or NHE1 in cardiomyocytes by a 38 transgenic inducible approach to test the hypothesis that activation of Na+/H+-exchange and/or anion-exchange can induce cardiac remodeling.