Aquaporin-4 in the heart: expression, regulation and functional role in ischemia
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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.
KeywordsAquaporins Myocardial infarction Edema Transgenic mice
Mubashar Amin and Bjørg Riber helped with quantitative immunogold, Torgeir Holen gave valuable advice regarding PCR technique and Western blot, Anna Thoren provided animals, and Torun Flatebø provided excellent technical assistance, all of which is gratefully acknowledged. This work was supported by Gjensidigestiftelsen, The Southeastern Regional Health Trust, The Jahre Foundation, The University of Oslo, and Oslo University Hospital—Ullevål, The Nansen Foundation, and the Norwegian Health Association. Lars Mariero is the recipient of a medical student’s scholarship from the University of Oslo and the Norwegian Research Council.
Conflict of interests
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