Mitochondriales Connexin 43: Regulation und Funktion

线粒体连接蛋白 43：调节和功能

• 批准号: 16789368
• 负责人: Professor Dr. Rainer Schulz
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/16789368?language=en
• 关键词: Mitochondriales; Connexin; 43; Regulation; und

Cardiomyocyte connexin43 (Cx43) plays a causal role in the cardioprotecion by ischemia preconditioning (IP), since infarct size reduction by IP is lost in heterozygous Cx43 deficient mice hearts and isolated cardiomyocytes. Apart from Cx43 being localized at the cardiomyocyte sarcolemma, we have demonstrated that Cx43 is present in mitochondria isolated from mice, rat, pig and human LV myocardium; the Cx43 content is higher in mitochondria isolated from preconditioned than from non-preconditioned myocardium. The exact localization of Cx43 within mitochondria and the mechanisms regulating its import or degradation are unknown. Therefore, signal transduction pathways will be stimulated by ischemia/reperfusion in isolated rat hearts and cardiomyocytes in the absence or presence of specific protein kinase (A,C,G or MAP kinase) inhibitors and rnitochondrial Cx43 levels and its exact localization (outer/inner membrane or matrix) will be measured. Alternatively, protein kinases will be stimulated by specific agonists and changes in mitochondrial Cx43 content will be assessed. To determine Cx43 function in mitochondria, its complete ablation will be induced in genetically modified mice (cre/flox) by the injection of 4-hydroxytamoxifen, and mitochondrial membrane potential, respiration, swelling, opening of the permeability transition pore and radical formation will be measured before and following ischemia/reperfusion; in the latter experimental setup, infarct size will be assessed separately in in vivo hearts.

心肌细胞连接蛋白43（Cx43）在缺血预处理（IP）的心脏保护作用中起着重要作用，因为在Cx43缺陷的杂合子小鼠心脏和分离的心肌细胞中，IP减少梗死面积的作用丧失。除了Cx43被定位在心肌细胞肌膜，我们已经证明，Cx43是存在于从小鼠，大鼠，猪和人LV心肌分离的线粒体中; Cx43含量高于从非预处理心肌分离的线粒体。Cx43在线粒体内的确切定位以及调节其输入或降解的机制尚不清楚。因此，在不存在或存在特异性蛋白激酶（A、C、G或MAP激酶）抑制剂的情况下，在分离的大鼠心脏和心肌细胞中通过缺血/再灌注刺激信号转导途径，并测量线粒体Cx43水平及其精确定位（外/内膜或基质）。或者，将通过特异性激动剂刺激蛋白激酶，并评估线粒体Cx43含量的变化。为了确定线粒体中的Cx43功能，将通过注射4-羟基他莫昔芬在遗传修饰的小鼠（cre/flox）中诱导其完全消融，并在缺血/再灌注之前和之后测量线粒体膜电位、呼吸、肿胀、渗透性转换孔的开放和自由基形成;在后一实验设置中，将在体内心脏中单独评估梗死面积。

项目成果

Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects

• DOI: 10.1007/s00395-012-0299-8
• 发表时间: 2012-09
• 期刊: Basic Research in Cardiology
• 影响因子: 9.5
• 作者: J. Schrickel;L. Lickfett;T. Lewalter;K. Tiemann;G. Nickenig;H. Baba;G. Heusch;R. Schulz;B. Levkau

Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria

• DOI: 10.1007/s00395-009-0007-5
• 发表时间: 2009-03-01
• 期刊: BASIC RESEARCH IN CARDIOLOGY
• 影响因子: 9.5
• 作者: Boengler, Kerstin;Stahlhofen, Sabine;Schulz, Rainer
• 通讯作者: Schulz, Rainer