Connexin43 as a determinant of arrhythmia inducibility in cardiac gap junction of infarct heart

Connexin43 作为梗塞心脏间隙连接诱导心律失常的决定因素

• 批准号: 14571286
• 负责人: KANNO Shigeto
• 金额: $ 1.73万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571286/
• 关键词: Gap Junction; Connexin43; Isohemia; Arrhythmia

Sudden cardiac death is common in patients who have survived myocardial infarction (MI), but the molecular mechanisms responsible are complex and poorly defined. To facilitate development of a mouse model to define gene products critical in lethal arrhythmia following MI, we created MI by LAD coronary occlusion in C57BL/6J mice heterozygous for a major gap junction protein Cx43 null allele and wildtype. To characterize structural consequences in MI, we used echocardiography. Left ventricular end-diastolic volume was increased as a function of infarct size at both 1 and 10 weeks after surgery. However, no differences in the relationship between left ventricular end-diastolic volume and infarct size were seen in wildtype and Cx43-deficient mice. Post-infarction remodeling as a function of infarct size was not affected by diminished Cx43 expression. Isolated hearts with healed MI were analyzed with extrastimulus protocol for inducing ventricular tachycardia (VT). VT was induced in both Cx … More 43+/-and +/+ hearts with MI. Ventricular sections were examined histologically. Infarct size was smaller in Cx43+/-mice compared with +/+ mice. Specific morphological features were evaluated including whether infarcts were transmural or non-transmural, and the presence or absence of ventricular aneurysmal dilatation, patchy interstitial fibrosis at infarct border zones, and surviving subendocardial myocytes. A layer of surviving subendocardial myocytes was seen more frequently in hearts in which VT could be induced but the occurrence of this feature was similar in Cx43+/-and +/+ hearts. The other features of post-infarct remodeling pertinent to development of arrhythmias and contractile dysfunction in hearts with healed infarcts were also observed with equal frequency in Cx43 +/-and +/+ hearts. Reduced basal coupling does not by itself significantly alter infarct healing or post-MI remodeling. Analysis of arrhythmias following MI in mouse lines with defined genetic defects will shed light on the roles of these proteins in sudden cardiac death in patients with healed MI. Less

心源性猝死在心肌梗死（MI）幸存的患者中很常见，但导致心源性猝死的分子机制很复杂且定义不清。为了促进小鼠模型的开发，以确定心肌梗死后致命性心律失常的关键基因产物，我们在C57 BL/6 J小鼠中通过LAD冠状动脉闭塞创建了心肌梗死，该小鼠为主要间隙连接蛋白Cx 43无效等位基因和野生型杂合子。为了表征心肌梗死的结构性后果，我们使用了超声心动图。左心室舒张末期容积在术后1周和10周均随梗死面积增加而增加。然而，在野生型和Cx43缺陷小鼠中，左心室舒张末期容积和梗死面积之间的关系没有差异。梗死后重构作为梗死面积的函数不受Cx43表达减少的影响。心肌梗死愈合的离体心脏采用室性心动过速（VT）诱导法进行分析。在两个Cx中诱导VT ...更多信息 43例+/-和+/+心脏MI。对心室切片进行组织学检查。与+/+小鼠相比，Cx43+/-小鼠中的血小板大小较小。具体的形态学特征进行了评价，包括是否梗死是透壁或非透壁，以及是否存在心室壁扩张，斑块间质纤维化在梗死边缘区，和存活的内膜下肌细胞。一层存活的内膜下心肌细胞在可诱导VT的心脏中更常见，但在Cx 43 +/-和+/+心脏中，这一特征的发生相似。在Cx43 +/-和+/+心脏中也观察到与已愈合梗死的心脏中心律失常和收缩功能障碍的发展相关的梗死后重构的其他特征，频率相同。降低基底偶联本身并不显著改变梗死愈合或MI后重塑。在具有确定遗传缺陷的小鼠系中分析MI后的心律失常将阐明这些蛋白在MI治愈患者的心源性猝死中的作用。少

项目成果

Shigeto Kanno, Attila Kovacs, Kathryn A.Yamada, Jeffrey E.Saffitz: "Connexin43 as a determinant of myocardial infarct size following coronary occulusion in mice"Journal of the American College of Cardiology. 41. 681-686 (2003)

Shigeto Kanno、Attila Kovacs、Kathryn A.Yamada、Jeffrey E.Saffitz：“Connexin43 作为小鼠冠状动脉闭塞后心肌梗塞大小的决定因素”美国心脏病学会杂志。

Shigeto Kanno, Deborah L.Lerner, Richard B.Schuessler, Tetsuo Betsuyaku, Kathryn A.Yamada, Jeffrey E.Saffitz, Attila Kovacs: "Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction"J Am Soc of Echocardiogr.. 15(6)

Shigeto Kanno、Deborah L.Lerner、Richard B.Schuessler、Tetsuo Betsuyaku、Kathryn A.Yamada、Jeffrey E.Saffitz、Attila Kovacs：“心肌梗塞小鼠模型心室重构的超声心动图评估”J Am Soc of Echocardiogr..

Shigeto Kanno: "Connexin43 as a determinantof myocardial infarct size following coronary occulusion in mice"Journal of the American College of Cardiology. 41. 681-686 (2003)

Shigeto Kanno：“Connexin43 作为小鼠冠状动脉闭塞后心肌梗塞大小的决定因素”美国心脏病学会杂志。

Shigeto Kanno: "The role of myocardial gap junctions in electrical conduction and arrhythmogenesis"Cardiovascular Pathology. 10. 169-177 (2001)

Shigeto Kanno：“心肌间隙连接在电传导和心律失常发生中的作用”心血管病理学。

Shigeto Kanno et al.: "Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction"J Am Soc of Echocardiogr. 15(6). 601-609 (2002)

Shigeto Kanno 等人：“心肌梗塞小鼠模型中心室重构的超声心动图评估”J Am Soc of Echocardiogr。