甲减导致房颤易感性增加，但机制尚不明确。我们前期在甲减诱发房颤的大鼠中发现T3减低时心房组织p65磷酸化水平及Arg-II表达增加，调控线粒体ATP合成的关键酶IDH活性下降，使ATP敏感型钾通道sarcKATP激活；并预测出T3可抑制p65磷酸化影响Arg-II表达，Arg-II与IDH辅酶NADP+均能特异结合IDH的Gly310-Thr325氨基酸序列。据此提出假设：甲减时T3下降，p65磷酸化上调，激活Arg-II表达，通过与NADP+竞争结合IDH使ATP合成减少，引起sarcKATP开放诱发房颤。为验证假设，本项目拟明确甲减时T3靶向调控p65活性、激活Arg-II表达的方式与位点，确认Arg-II竞争拮抗线粒体IDH/ATP对sarcKATP通道的影响，阐明T3/p65/Arg-II/IDH/sarcKATP途径在甲减介导房颤中的作用，为揭示甲减诱发房颤的分子机制提供新思路。

Hypothyroidism will increase the susceptibility of atrial fibrillation (AF), but the corresponding mechanism is unclear. In our previous studies, detections in rats with hypothyroidism-induced AF revealed increased phosphorylation level of nuclear transcription factor p65, enhanced expression of arginase-II (Arg-II), reduced activity of isocitrate dehydrogenase (IDH), a key enzyme that controlled mitochondrial ATP synthesis, and significant activation of sarcolemmal KATP (sarc KATP) channels in atrial myocytes. Bioinformatics prediction indicated that triiodothyronine (T3) could negatively regulate Arg-II expression by specifically binding to the phosphorylation site of p65. In addition, both Arg-II and NADP+ (the coenzyme of IDH) were able to combine with the amino acid sequence of Gly310-Thr325 in the active pocket domain of IDH. Therefore, we hypothesize that decreased levels of T3 during hypothyroidism will stimulate the up-regulation of p65 phosphorylation as well as the activation of Arg-II expression. The elevated Arg-II will antagonize the activity of IDH by combining with it through the competition with NADP+, leading to reduced synthesis of ATP in mitochondria, activated sarc KATP channels in atrial myocytes, and shortened action potential duration predisposing to AF. In this project, we will identify the effect and site by which decreased T3 stimulates Arg-II expression through the targeted regulation of p65, confirm the influence of Arg-II antagonizing mitochondrial IDH/ATP metabolism on sarc KATP channels, and ultimately elucidate the role of T3/p65/Arg-II/IDH/sarc KATP pathway in hypothyroidism-induced AF. The current study will provide us with new insights into the potential molecular mechanism of AF induced by hypothyroidism.