AQP4 knockout mice manifest abnormal expressions of calcium handling proteins possibly due to exacerbating pro-inflammatory factors in the heart.
We tested the hypothesis that aquaporin-4 (AQP4) knockout (KO) mice might exhibit abnormal Ca(2+) modulating proteins resulting from the exacerbation of pro-inflammatory factors in the heart. Downregulation of FKBP12.6, SERCA2a, and CASQ2 and calcium leak in diastole have been recognized as endpoints for assessing cardiac failure and arrhythmias. The AQP4 KO mice and wild-type (WT) mice were randomly divided into 3 groups, such as control, isoproterenol (ISO, β-receptor agonist) injected (1 mg/kg, sc, 5 d), and treated with aminoguanidine (AMG, 100 mg/kg, po, a selective inhibitor of the iNOS) during the last 3d. RT-PCR, western blot and calcium transient measurements were conducted. The results demonstrated that the cardiac weight index was increased in AQP4 KO mice and further increased following treatment with ISO. The expression levels of FKBP12.6, SERCA2a, and CASQ2 were downregulated and diastolic calcium concentrations were elevated in the AQP4 KO mice, indicative of a calcium leak. In the myocardium, expressions of pro-inflammatory biomarkers, including ET(A), pPKCɛ, NADPH oxidase p67(phox) were upregulated and associated with downregulation of Cx43. The aforementioned changes were exacerbated in response to ISO medication and were attenuated by AMG; however, its treatment effectiveness was less in the AQP4 KO mice. We concluded AQP4 KO caused abnormalities of calcium modulating proteins leading to an exacerbation of risk for cardiac arrhythmias and failure. These changes are likely due to an increase in pro-inflammatory factors which are exacerbated by stress. Therefore, AQP4 KO mice are prone to cardiac failure and arrhythmias through exacerbating pro-inflammatory factors in the myocardium.
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
Yu-Si
YS
Cheng
Yi-Qun
YQ
Tang
De-Zai
DZ
Dai
Yin
Y
Dai
D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency* / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D018836:Inflammation Mediators; D002118:Calcium