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Cardioprotection with nuclear-targeted Akt/PKB

核靶向 Akt/PKB 的心脏保护作用

基本信息

批准号：
17591106
负责人：
SHIRAISHI Isao
金额：
$ 2.3万
依托单位：
Kyoto Prefectural University of Medicine
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

项目摘要

Heart failure is associated with death of cardiomyocytes leading to loss of contractility. Previous studies using membrane-targeted Akt (myristolated-Akt), an enzyme involved in antiapoptotic signaling, showed inhibition of cell death and prevention of pathogenesis induced by cardiomyopathic stimuli. However, recent studies by our group have found accumulation of activated Akt in the nucleus, suggesting that biologically relevant target(s) of Akt activity may be located there. To test this hypothesis, a targeted Akt construct was created to determine the antiapoptotic action of nuclear Akt accumulation. Nuclear localization of the adenovirally encoded Akt construct was confirmed by confocal microscopy. Cardiomyocytes expressing nuclear-targeted Akt showed no evidence of morphological remodeling such as altered myofibril density or hypertrophy. Nuclear-targeted Akt significantly elevated levels of phospho-Akt and kinase activity and inhibited apoptosis as effectively as myristolated-Akt in hypoxia-induced cell death. Transgenic overexpression of nuclear-targeted Akt did not result in hypertrophic remodeling, altered cardiomyocyte DNA content or nucleation, or enhanced phosphorylation of typical cytoplasmic Akt substrates, yet transgenic hearts were protected from ischemia-reperfusion injury. Gene array analyses demonstrated changes in the transcriptional profile of Akt/nuc hearts compared with nontransgenic controls distinct from prior characterizations of Akt expression in transgenic hearts. Collectively, these experiments show that targeting of Akt to the nucleus mediates inhibition of apoptosis without hypertrophic remodeling, opening new possibilities for therapeutic applications of nuclear-targeted Akt to inhibit cell death associated with heart disease.

心力衰竭与心肌细胞死亡相关，导致收缩力丧失。以前的研究使用膜靶向Akt（myristolated-Akt），一种参与抗凋亡信号传导的酶，显示出抑制细胞死亡和预防心肌病刺激诱导的发病机制。然而，我们小组最近的研究发现激活的Akt在细胞核中积累，这表明Akt活性的生物学相关靶标可能位于那里。为了验证这一假设，建立了一个靶向Akt构建体，以确定细胞核Akt积累的抗凋亡作用。通过共聚焦显微镜证实腺病毒编码的Akt构建体的核定位。表达核靶向Akt的心肌细胞没有表现出形态重塑的证据，如肌原纤维密度改变或肥大。核靶向Akt显著升高磷酸化Akt水平和激酶活性，并在缺氧诱导的细胞死亡中与肉豆蔻醇化Akt一样有效地抑制细胞凋亡。核靶向Akt的转基因过表达并不导致肥厚性重塑、改变心肌细胞DNA含量或成核、或增强典型细胞质Akt底物的磷酸化，但转基因心脏可免受缺血再灌注损伤。基因阵列分析表明，Akt/nuc心脏的转录谱的变化与非转基因对照不同，从以前的特征Akt在转基因心脏的表达。总的来说，这些实验表明，Akt靶向细胞核介导的细胞凋亡的抑制，而没有肥厚性重塑，开辟了新的可能性，治疗应用核靶向Akt抑制与心脏病相关的细胞死亡。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A case in a child of giant left-atrial myxoma associated with recurrent high fever and myxoma cells expressing interleukin-6

DOI：
10.1007/s00431-005-0061-4
发表时间：
2006-05-01
期刊：
EUROPEAN JOURNAL OF PEDIATRICS
影响因子：
3.6
作者：
Shiraishi, I;Yamagishi, M;Hamaoka, K
通讯作者：
Hamaoka, K

Stereolithgraphic biomodeling of congenital heart disease by using volumetric data obtained from multi-slice CT

使用多层 CT 获得的体积数据对先天性心脏病进行立体光刻生物建模

DOI：
发表时间：
2006
期刊：
Circulation. 113(5)(in press)
影响因子：
0
作者：
Shiraishi I;Kajiyama Y;Yamagishi Hamaoka K
通讯作者：
Yamagishi Hamaoka K

Long-term changes in coronary artery aneurysms in patients with Kawasaki disease - Comparison of therapeutic regimens

DOI：
10.1253/circj.69.265
发表时间：
2005-03-01
期刊：
CIRCULATION JOURNAL
影响因子：
3.3
作者：
Onouchi, Z;Hamaoka, K;Kiyosawa, N
通讯作者：
Kiyosawa, N

Teratogenic effects of bis-diamine on the developing cardiac conduction system.

双二胺对发育中的心脏传导系统的致畸作用。

DOI：
发表时间：
2006
期刊：
Birth Defects Res A Clin Mol Teratol. 73(8)
影响因子：
0
作者：
Kise K;Nakagawa M;Okamoto N;Hanato T;Watanabe N;Nishijima S;Fujino H;Takeuchi Y;Shiraishi I
通讯作者：
Shiraishi I

Severe heart failure due to subacute effusive-constrictive pericarditis in a child.

儿童亚急性渗出性缩窄性心包炎导致的严重心力衰竭。