Significance of an activation of PKC in remodeling of connexin 43 of the cardiac gap junction channel

PKC 激活在心脏间隙连接通道连接蛋白 43 重塑中的意义

• 批准号: 17500280
• 负责人: IMANAGA Issei
• 金额: $ 1.6万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500280/
• 关键词: cardiac muscle cell; gap junction; connexin 43; PKC; remodeling; ventricular fibrillation; ギャップ結合

Functional regulation of gap junction which essentially contributes to intercellular impulse propagation depends on phosphorylation of connexin composing the gap junction channel. 2 main factors of phosphorylation are intracellular signal of PKA and PKC. In this study, Remodeling of connexin 43 (Cx43) by PKA or PKC and relationship the remodeling of Cx43 and susceptibility of the heart to arrhythmias (aconitine-induced ventricular fibrillation) were examined on isolated rat or guinea-pig hearts using methods of electrophysiology, immunoblot and immunohistochemistry.In the PMA treated heart, the diabetic heart (STZ-induced rat : Type I, OLETF, GK rat : TypeII), an acceleration of activity of PKC ε, an augmentation of the PKC ε-mediated phosphorylation of Cx43 and a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area, an increase in ventricular tissue Angiotensin II (AngII) level were observed in association with electrical cell-to-cell decoupli … More ng. These downward remodeling of Cx43 were ameliorated by PKC inhibitors, Proteasomal inhibitors or Lysosomal inhibitors. In the hypoxic heart, a reduction of the PKA-mediated phosphorylation, a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area were observed in association of electrical cell-to-cell decoupling. These downward remodeling of Cx43 ware restored by PKA activators.On the mechanism of generation of tachyarrhythmias, such as, ventricular fibrillation (VF), both acceleration of automatic activity and electrical interaction between neighboring cells (microreentry) caused by disturbances of the gap junction are essentially involved. In this meanings, dysfunction of the gap junction contributes to generation of the cardiac fibrillation. After application of aconitine, the electrical fluttering activity was spontaneously followed by VF. At the beginning of VF, an acceleration of activity of PKC ε, a reduction of the PKA-mediated phosphorylation, an augmentation of PKC ε- mediated phosphorylation of Cx43 and a decrease in quantity of Cx43 protein, heterogenous expression of Cx43 at the gap junction area, an increase in ventricular tissue AngII level were observed with irregular interaction of electrical activity between neighboring cells. These changes were promoted as VF advanced.In the diabetic heart (Type I, II), the PMA-treated or the Ang. II analog-treated heart, susceptibility to VF was remarkably augmented. These effects were abolished by PKC inhibitors, Ang. II receptor antagonists or proteolytic inhibitors. In the hypoxic heart, also, generation of fibrillation was accelerated. On the other hand, PKA activators cyclic AMP analog prevented the initiation of W with an increase in quantity and expression of Cx43.It is concluded that the downward remodeling of Cx43 contributes to generation of VF forming substrate for reentry. The downward remodeling of Cx43 is induced by the PKC E-mediated hyperphosphorylation and dephosphorylation of the PKA-mediated residue of Cx43, and is promoted by VF itself. It is suggested that in clinical implication, PKA activators, PKC inhibitors or Ang II blockers prevent or ihibit generation of VF. Less

缝隙连接的功能调控主要依赖于构成差距连接通道的连接蛋白的磷酸化。磷酸化的2个主要因素是PKA和PKC的胞内信号。本研究探讨了PKA、PKC对连接蛋白43（Cx43）的重构及其与心律失常易感性的关系本研究应用电生理、免疫印迹和免疫组织化学方法，在离体大鼠和豚鼠心脏上观察了乌头碱诱发的糖尿病性室颤（ACV）。（STZ诱导大鼠：I型，OLETF，GK大鼠：II型），PKC ε活性增强，PKC ε介导的Cx43磷酸化增强，Cx43蛋白量减少，Cx43在差距连接区异源表达，观察到心室组织血管紧张素II（AngII）水平的增加与细胞间电刺激有关， ...更多信息 ng. PKC抑制剂、蛋白酶体抑制剂或溶酶体抑制剂可改善Cx43的这些向下重构。缺氧心肌细胞间电去偶联导致PKA介导的磷酸化水平降低，Cx43蛋白表达减少，差距连接区Cx43表达异源。在快速性心律失常如心室颤动（ventricular fibrillation，VF）的发生机制中，差距连接紊乱引起的自主活动加速和相邻细胞间的电相互作用（微折返）是主要的机制。在这个意义上，差距连接的功能障碍有助于心脏纤颤的产生。应用乌头碱后，电扑动活动自发地跟随VF。VF开始时，PKC ε活性增强，PKC介导的磷酸化减少，PKC ε介导的Cx43磷酸化增强，Cx43蛋白含量减少，Cx43在差距连接区异源表达，心室组织AngII水平升高，相邻细胞间电活动相互作用不规则。在糖尿病心脏（I型、II型），PMA处理组或Ang. II类似物治疗的心脏，VF的易感性显着增加。这些作用被PKC抑制剂Ang阻断。II受体拮抗剂或蛋白水解抑制剂。在缺氧心脏中，也加速了纤颤的产生。PKA激活剂cAMP类似物可抑制W的起始，并增加Cx43的表达和数量。结论：Cx43的向下重构有助于VF形成基质的产生。Cx43的向下重构是由PKC E介导的Cx43残基的过度磷酸化和PKA介导的Cx43残基的去磷酸化诱导的，并且VF本身促进Cx43的向下重构。提示PKA激活剂、PKC抑制剂或Ang Ⅱ阻断剂可预防或抑制VF的发生。少

项目成果

PKC-Induced Remodeling of cardiac gap junction connexin 43 and arrhythmogenesis

PKC 诱导的心脏间隙连接连接蛋白 43 重塑和心律失常发生

• 发表时间: 2006
• 期刊: Chinese J Pathophysiol 22(13)
• 作者: T.Liu;et al.;Imanaga I et al.
• 通讯作者: Imanaga I et al.

Effects of cyclic AMP on the cardiac gap junction function during hypoxia

缺氧时环磷酸腺苷对心脏间隙连接功能的影响

• 发表时间: 2006
• 期刊: Exp Clin Cardiol 11
• 作者: Tajashi Mayama;et al.;Hai Lin et al.;Hai Lin et al.;Ken Matsumura et al.
• 通讯作者: Ken Matsumura et al.

Remodeling of connexin 43 in the diabetic rat heart

• DOI: 10.1007/s11010-006-9166-y
• 发表时间: 2006-10-01
• 期刊: MOLECULAR AND CELLULAR BIOCHEMISTRY
• 影响因子: 4.3
• 作者: Lin, Hai;Ogawa, Koichi;Tribulova, Narcis
• 通讯作者: Tribulova, Narcis

糖尿病ラット心筋におけるCx43のremodeling

Cx43在糖尿病大鼠心肌中的重构

• 发表时间: 2005
• 期刊: 第4回コネキシン研究会 抄録
• 作者: T.Nakatsuka;et al.;Hai Lin;今永一成;海 琳
• 通讯作者: 海 琳

The remodeling of the gap junction makes the heart susceptible to arrhythmias

间隙连接的重塑使心脏容易出现心律失常

• 发表时间: 2005
• 期刊: The 5^<th>. Japan-Korea Joint Symposium on Brain Sciences, and Cardiac and Smooth Muscles abstract
• 作者: T.Nakatsuka;et al.;Hai Lin;今永一成;海 琳;I.Imanaga
• 通讯作者: I.Imanaga