Analysis of Molecular Mechanisms Underlying the Initiation and Perpetuation of Tachyarrhythmias

心肌细胞通过由连接蛋白组成的间隙连接通道在电和代谢方面相互连接。许多动物和人体研究已经描述了在多种病理条件下连接蛋白丰度或亚细胞定位的改变，包括肥厚、心力衰竭、缺血性心脏病和心房颤动。许多连接蛋白，包括在心脏中表达最丰富的连接蛋白43 (Cx43)，其半衰期很短，为1 ~ 5小时，反映了它们通过合成和降解的快速更新。1)我们检测了心房颤动（MVD/AF）或正常窦性心律（MVD/NSR）的MVD（二尖瓣疾病）患者右心房心肌中连接蛋白（Cx）40和Cx43蛋白及mrna的相对表达水平。Cx40组的MVD/AF明显低于MVD/NSR组或对照组（非MVD伴NSR患者），而Cx43组间差异不显著。MVD/AF组蛋白磷酸化的Cx40比对照组高52%。在人心房中，Cx40下调和丝氨酸磷酸化增加可能扭曲细胞间通讯并改变电生理，导致af的发生和/或持续。2)我们研究了快速电刺激（RES）对培养的新生大鼠心室肌细胞Cx43间隙连接表达的影响，以及由此引起的传导特性的变化。对培养的心室肌细胞进行60 ~ 120 min的快速收缩电刺激（RES）可使Cx43 mRNA和蛋白表达增加。这与培养基中AngII的增加和ERK、JNK和p38 MAPKs活化形式的上调有关。细胞外电位图显示传导速度增加。氯沙坦可以预防RES的大多数这些影响。短期收缩的RES通过AngII的自分泌作用激活MAPKs，引起Cx43的上调和伴随的传导特性的改变。少

Cardiac myocytes are connected with each other electrically and metabolically through gap junction channels composed of connexins. Many animal and human studies have described alterations in the abundance or subcellular localization of connexin proteins under a variety of pathological conditions including hypertrophy, heart failure, ischemic heart diseases, and atrial fibrillation. Many connexins, including connexin43 (Cx43), which is expressed most abundantly in the heart, have short half-lives of 1〜5 hours reflecting their rapid turnover through synthesis and degradation.1)We examined the relative expression levels of connexin (Cx)40 and Cx43 protein and mRNAs in the right atrial myocardium from MVD (mitral valvular disease) patients with either atrial fibrillation (MVD/AF) or normal sinus rhythm (MVD/NSR). For Cx40, there were significantly lower in MVD/AF than that in MVD/NSR or in the controls (non-MVD patients with NSR), but for Cx43 showed insignificant intergroup differences. S … More erine-phosphorylated Cx40 was 〜52% greater in MVD/AF than in the controls. In human atria, Cx40 down-regulation and increased serine-phosphorylation may distort cell-to-cell communication and alter electrophysiology, leading to initiation and/or perpetuation of AF.2)We investigated the effects of rapid electrical stimulation (RES) on the expression of Cx43 gap junction in neonatal rat cultured ventricular myocytes, and consequent changes of conduction properties. Application of rapid electrical stimulation (RES) of contraction for 60-120 min to cultured ventricular myocytes resulted in an increase of Cx43 expression (mRNA and protein). This was associated with an increase of AngII in the culture media and upregulation of activated forms of ERK, JNK and p38 MAPKs. Extracellular potential mapping revealed an increase of conduction velocity. Most of these effects of RES were prevented by losartan. A short-term RES of contraction causes upregulation of Cx43 and concomitant alterations of conduction properties through an autocrine action of AngII to activate MAPKs. Less