2006 Fiscal Year Final Research Report Summary
Gap Junction Remodeling and Renin-Angiotensin-Aldosterone System
| Project/Area Number |
17590738
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Yamaguchi University |
|---|
Principal Investigator |
OHKUSA TOMOKO Yamaguchi University, Graduate School of Medicine, Research Asscciate, 大学院医学研究科, 助手 (00294629)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MATSUZAKI Masunori Yamaguchi University, Graduate School of Medicine, Professor, 大学院医学研究科, 教授 (60116754)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Keywords | tachyarrhythmia / gap junction / connexin / rennin-angiotensin-aldosterone system / electrical coupling / electrical propagation |
|---|
| Research Abstract |
Electrical coupling in the heart is mediated by cardiac gap junctions. The expression and distribution of gap junctions can be easily changed under a variety of pathological conditions because of dynamic turnover of connexins (Cxs), and gap junctions are considered to be an important factor in the origin of lethal reentrant arrhythmias. Here, we investigated 1) the alterations in connexin (Cx) as an arrhythmogenic substrate in cardiomyocytes from patients with chronic atrial fibrillation (AF), cultured ventricular myocytes exposed to rapid electrical stimulation (RES), and animal model of heart failure, 2) the contribution of renin angiotensin aldosterone system (RAAS) to GJ remodeling, and 3) whether the regulation of RAAS will be a new upstream therapy for the treatment of arrhythmias. In patients with AF, downregulation and abnormal phospholylation of Cx40 may result in abnormal cell-to-cell communication and alteration in the electrophysiologic properties, leading to the initiation and/or perpetuation of AF. Moreover, a short-term RES caused upregulation of Cx43 in cardiomyocytes and a concomitant increased of conduction velocity, mainly through an autocrine action of angiotensin II to activate MAKP. During the development of heart failure, in addition to interstitial fibrosis, down-regulation and abnormal serine-phosphorylation of Cx43 resulted in abnormal cell-to-cell communication and alteration in the electrophysiologic properties of the ventricle, leading to the initiation and perpetuation of ventricular arrythmias. Our results suggest that gap junction remodeling might be an important arrhythmogenic substrate, therefore upstream approach which prevents the gap junction remodeling should be considered as an alternative strategem to traditional treatment with membrane-active anti-arrhythmic agents.
|
