Cardiac characteristics of transgenic mice overexpressing Refsum disease gene-associated protein within the heart

Arrhythmia is a common cardiac symptom of Refsum disease. Recently, we iden tified a novel neuron-specific PAHX-associated protein (PAHX-AP1), which bi nds to the Refsum disease gene (PAHX). In this report, we developed heart-t argeted transgenic (TG) mice under the control of alpha -myosin heavy chain promoter to determine whether cardiac overexpression of PAHX-AP1 provokes cardiac involvement symptoms. Northern and in situ hybridization analyses r evealed PAHX-AP1 transcript was overexpressed in TG atrium, especially in t he sinoatrial node. TG mice showed tachycardia, and tachyarrhythmia was obs erved in 20% of TG mice. Isolated TG atria showed higher frequency beating and were more sensitive to aconitine-induced tachyarrhythmia than the wild- type, and 40% of the TG atria showed irregular beating. Action potential du ration in TG atrial fiber was shortened much more than the wild-type. Syste mic administration of arrhythmogenic agents induced arrhythmia in TG mice, while no arrhythmia with the same dose in nonTG mice. Our results indicate that the chronic atrial tachycardia by overexpressed neuron-specific PAHX-A P1 transgene in atrium may be responsible for the increased susceptibility to arrhythmia. (C) 2001 Academic Press.