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

Abstract

Aquaporins (AQPs) are channel-forming membrane proteins highly permeable to water. AQP4 is found in mammalian hearts; however, its expression sites, regulation and function are largely unknown. The aim was to investigate cardiac AQP4 expression in humans and mice, its regulation by ischemia and hypoxia, and in particular its role in cardiac ischemic injury using AQP4 knockout (KO) mice. Comparable levels of AQP4 were detected by Western blot and qPCR in biopsies from human donor hearts and wild type C57Bl6 mouse hearts. In mice, AQP4 was expressed on cardiomyocyte plasmalemma (qPCR, Western blot, immunogold), and its mRNA decreased following ischemia/reperfusion (isolated hearts, p = 0.02) and after normobaric hypoxia in vivo (oxygen fraction 10 % for 1 week, p < 0.001). Isolated hearts from AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size (p = 0.05) and attenuated left ventricular end-diastolic pressure during reperfusion (p = 0.04). Infarct size was also reduced in AQP4 KO mice 24 h after left coronary artery ligation in vivo (p = 0.036). AQP4 KO hearts had no compensatory change in AQP1 protein expression. AQP4 KO cardiomyocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture. AQP4 is expressed in human and mouse hearts, in the latter confined to the cardiomyocyte plasmalemma. AQP4 mRNA expression is downregulated by hypoxia and ischemia. Deletion of AQP4 is protective in acute myocardial ischemia-reperfusion, and this molecule might be a future target in the treatment of acute myocardial infarction.

Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia

“…Based on the demonstrated role of AQP4 during brain and heart ischemia (14, 26), we hypothesized that AQP4 blockade ameliorates the consequences of ischemia reperfusion injury and thus extends transplant survival. Unexpectedly, AQP4 inhibition did not alter the intragraft expression of inflammatory markers typically found in ischemia/reperfusion injury at 24 h posttranspant including cytokines TNFα, IL-1β, IL-6, chemokines CXCL1, CXCL2, and CCL2, and adhesion molecule ICAM-1 (Figure 3A).…”

“…Our study was prompted by recent findings that AQP4 is expressed on cardiac myocytes and is protective during ischemic cardiac tissue injury (14). Treatment of donor hearts with the AQP4 inhibitor during collection, perfusion and storage significantly reduced the rate of cellular apoptosis.…”

“…AQP4 is also expressed by cardiomyocytes, and AQP4 deficiency results in reduced myocardial tissue damage and edema during infarct (14, 15). These findings suggest that blocking AQP4 may attenuate IRI as well as innate and adaptive immune responses following transplantation.…”

On the Role of Aquaporins in Myocardial Injury

“…Other works demonstrated that AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size and attenuated left ventricular end-diastolic pressure during reperfusion after cardiac ischemic injury [15]. Also AQP4 KO cardio-myocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture of the left coronary artery [15]. Other evidences indicate that Diazoxide (a mitochondrial KATPchannel opener) may have impact on myocardial water balance and glycerol uptake by decreasing the relative expression of AQP7 during coronary artery bypass grafting in patients with stable coronary artery disease [16].…”

“…These changes are likely due to an increase in pro-inflammatory factors (ET A , pPKCε, NADPH oxidase p67phox) which are exacerbated by stress [14]. Other works demonstrated that AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size and attenuated left ventricular end-diastolic pressure during reperfusion after cardiac ischemic injury [15]. Also AQP4 KO cardio-myocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture of the left coronary artery [15].…”