Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system.
Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system.
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DOI：
10.1126/scitranslmed.3009027
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发表时间：
2014-09-24
影响因子：
17.1
通讯作者：
Wu JC
中科院分区：
文献类型：
--
作者：
Ebert AD;Kodo K;Liang P;Wu H;Huber BC;Riegler J;Churko J;Lee J;de Almeida P;Lan F;Diecke S;Burridge PW;Gold JD;Mochly-Rosen D;Wu JC
近8%的人在编码心脏保护酶醛脱氢酶2 （ALDH2）的基因上携带失活点突变。这种基因多态性（ALDH2*2）与更严重的缺血性心脏损伤和冠状动脉疾病（CAD）风险增加有关，但其潜在的分子基础尚不清楚。我们研究了携带ALDH2*2基因型最常见杂合形式的个体产生的诱导多能干细胞衍生心肌细胞（iPSC-CMs）的人类模型系统中的ALDH2*2机制。我们发现ALDH2*2突变引起活性氧和有毒醛的增加，从而诱导细胞周期阻滞和凋亡信号通路的激活，特别是在缺血性损伤期间。我们发现ALDH2通过调节氧化应激水平来控制细胞的存活决定，而在功能缺失的ALDH2*2基因型中，这种调节回路功能失调，导致缺血损伤后心肌细胞凋亡上调。这些结果揭示了代谢酶ALDH2在调节细胞生存决定中的新功能。深入了解介导ALDH2*2相关的缺血性损伤增加的分子机制对于开发特定的CAD诊断方法和改善风险管理具有重要意义，并可能导致患者特异性心脏治疗。
Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation gave rise to elevated amounts of reactive oxygen species and toxic aldehydes, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. We established that ALDH2 controls cell survival decisions by modulating oxidative stress levels and that this regulatory circuitry was dysfunctional in the loss-of-function ALDH2*2 genotype, causing up-regulation of apoptosis in cardiomyocytes after ischemic insult. These results reveal a new function for the metabolic enzyme ALDH2 in modulation of cell survival decisions. Insight into the molecular mechanisms that mediate ALDH2*2-related increased ischemic damage is important for the development of specific diagnostic methods and improved risk management of CAD and may lead to patient-specific cardiac therapies.
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DOI：
10.1074/jbc.m109.014548
发表时间：
2010-01-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Beretta M;Gorren AC;Wenzl MV;Weis R;Russwurm M;Koesling D;Schmidt K;Mayer B
通讯作者：
Mayer B
影响因子：
56.9
作者：
Lee, SH;Oe, T;Blair, IA
通讯作者：
Blair, IA
影响因子：
5.2
作者：
Hu, Shijun;Wilson, Kitchener D.;Ghosh, Zhumur;Han, Leng;Wang, Yongming;Lan, Feng;Ransohoff, Katherine J.;Burridge, Paul;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
10.8
作者：
Gomes, Katia M. S.;Campos, Juliane C.;Ferreira, Julio C. B.
通讯作者：
Ferreira, Julio C. B.
影响因子：
4.8
作者：
Barr, RK;Kendrick, TS;Bogoyevitch, MA
通讯作者：
Bogoyevitch, MA