Upregulation of the Water Channel Aquaporin-4 as a Potential Cause of Postischemic Cell Swelling in a Murine Model of Myocardial Infarction

Abstract

Ischemia of the myocardium is generally accepted to be characterized by swelling of myocytes resulting in cardiac dysfunction. However, data are limited concerning the molecular mechanisms of fast water fluxes across cell membranes in ischemic hearts. Since aquaporin-4 (AQP4) is a water channel with an enormous water flux capacity, we investigated in this study whether this water channel protein might play a role in myocyte swelling following myocardial infarction. For this purpose, we studied the expression of AQP4 mRNA at different time points of ischemia in a murine model of myocardial infarction. We observed a significant correlation between the upregulation of AQP4 mRNA and the size of the infarction. In situ hybridization experiments showed comparably higher expression levels of AQP4 mRNA in ischemic myocytes, and anti-AQP4 immunoreactivity was found to be stronger in the sarcolemma of ischemic myocytes. Our findings imply a role of AQP4 in the formation of myocardial edema and this might be important for future prevention and treatment strategies of this distressing situation in order to minimize cardiac dysfunction and mortality in a variety of cardiac diseases in which cell swelling is prevalent.

Aquaporin-4 in the heart: expression, regulation and functional role in ischemia

“…Thus, it is currently unclear in which cardiac cells AQP4 is located, where in the cell it is expressed, and how its expression is regulated. AQP4 mRNA was previously found to increase during ischemia in murine hearts, although the implication of this finding was not evident [44]. A careful determination of AQP4 cellular and subcellular localization and its expression pattern will facilitate understanding the function of AQP4 in the heart.…”

“…AQP4 expression in the human heart was reported to be very low [7]. Only a few studies have addressed the expression and subcellular localization of AQP4 in the heart, with inconsistent results [7,38,44]. Thus, it is currently unclear in which cardiac cells AQP4 is located, where in the cell it is expressed, and how its expression is regulated.…”

Aquaporin-4 expression is severely reduced in human sarcoglycanopathies and dysferlinopathies

“…No expression was found in smooth muscle. 29,30 Our group and others indicated that AQP4 expression is decreased in patients affected by DMD and BMD. Although Crosbie et al, reported that AQP4 is reduced also in α-δ sarcoglycan knock-out mice, the regulation of this protein in human sarcoglycanopathies is not known.…”

Cardiac Aquaporins: Significance in Health and Disease

“…Transcriptional regulation of AQPs is seen in the heart [53,82,83] and it is tempting to speculate that cardiac AQPs could be a therapeutic target to improve the outcome of ischaemic injury. Cardiac AQP4 expression has been reported to increase following focal ischaemia in the mouse [84]. The response appears to be associated with irreversible ischaemic damage and also occurs in rat and human heart, in which AQP4 is not normally detectable (Butler and Winlaw, unpublished data).…”