Atrial Fibrillation and electrophysiology in Transgenic Mice with Cardiac-Restricted Overexpression of FKBP12

Zhenwei Pan, Tomohiko Ai, Po-Cheng Chang, Ying Liu, Jijia Liu, Mitsunori Maruyama, Mohamed Homsi, Michael C Fishbein, Michael Rubart, Shien-Fong Lin, Deyong Xiao, Hanying Chen, Peng-Sheng Chen, Weinian Shou, Bai-Yan Li
American Journal of Physiology. Heart and Circulatory Physiology 2018 November 30
Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC -FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. Patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. The channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in 4 of 7 αMyHC-FKBP12 mice, but in none of 8 nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts when compared to NTG hearts. Interestingly, the mean APD50 , but not APD90 , was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, the average peak INa density was dramatically reduced and the INa inactivation curve was shifted by ~+7 mV in αMyHC-FKBP12 atrial myocytes, while the activation and recovery curves were unaltered. Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav 1.2 protein levels and peak ICa,L density, and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces atrial Nav1.5 expression level and the mean peak INa , which is associated with increased peak ICa,L . and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitate the development of local conduction block, altered APD and spontaneous AF.

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