Role of AE3 and NHE1 in cardiomyocyte homeostasis and remodeling

心肌细胞中Na+/H+交换的刺激是心脏病理学中的常见特征。值得注意的是，Na+/H+-交换剂NHE 1的活化不一定需要pHi的下降，因为它可以通过阴离子交换剂AE 3的诱导来平衡。这种同时激活被认为提高细胞内Na+浓度，从而抑制Na+/Ca 2+交换。伴随的细胞内Ca 2+蓄积则可促进心肌肥大。事实上，NHE 1抑制剂在不同的动物研究中对心脏重塑有积极作用。由于NHE 1和AE 3之间的功能相互作用，我们解决了AE 3在完整和患病心脏中的作用。我们已经产生了组成型AE 3基因敲除小鼠，这表明心脏与体重比显着降低。我们现在建立了一个floxed Ae 3小鼠，这将使我们能够在心脏中特异性地破坏AE 3。该小鼠的体内表征将包括心电图、血压和超声心动图。体外分析将涵盖心脏重量、组织学、细胞内Na+浓度、心肌细胞收缩性、pHi和Ca 2+瞬变的调节。由于AE 3的作用，我们随后将评估AE 3不存在下的心脏重塑模型。同时，我们将通过转基因诱导方法在心肌细胞中过表达AE 3和/或NHE 1，以测试Na+/H+交换和/或阴离子交换的激活可以诱导心脏重塑的假设。

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.