The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.
The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.
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DOI：
10.1016/j.ebiom.2017.11.012
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发表时间：
2017-12
期刊：
影响因子：
11.1
通讯作者：
Ramasamy R
中科院分区：
文献类型：
--
作者：
O'Shea KM;Ananthakrishnan R;Li Q;Quadri N;Thiagarajan D;Sreejit G;Wang L;Zirpoli H;Aranda JF;Alberts AS;Schmidt AM;Ramasamy R
缺血心肌细胞内发生的生物化学、离子和信号传导变化因再灌注而加剧;然而，介导心肌缺血/再灌注（I/R）损伤的确切机制尚未完全阐明。晚期糖基化终末产物受体（receptor for advanced glycation end-products，RECEPTOR）调节I/R中对心脏组织损伤的细胞反应，这种作用可能由RECEPTOR胞质结构域与透明相关的受体DIAPH 1结合介导。本研究旨在探讨DIAPH 1在小鼠实验性心肌I/R生理反应中的作用。在野生型小鼠进行实验性I/R后，心肌DIAPH 1表达增加，这一效应在H9 C2和AC 16细胞中的缺氧/复氧（H/R）后得到了回应。此外，与野生型小鼠相比，Diaph 1基因缺失减少了I/R后的梗死面积并改善了收缩功能。在H/R下调肌动蛋白聚合和血清反应因子调节的基因表达的H9 C2细胞中沉默Diaph 1重要的是，这些变化导致肌浆网Ca 2 + ATP酶表达增加和钠钙交换器表达减少。这项工作表明，DIAPH 1是心肌对I/R的反应所必需的，并且靶向DIAPH 1可能代表急性梗死后心肌挽救的一种有效方法。DIAPH 1是心脏缺血/再灌注损伤的关键介质。Diaph 1缺失调节转录因子，血清反应因子，导致心肌细胞钙转运蛋白的调节。Diaph 1缺失的作用与短期缺血/再灌注损伤后收缩功能的改善相关，使其成为治疗进展性心肌梗死的潜在连续治疗靶点。尽管使用溶栓剂的再灌注疗法已成为治疗心肌梗死患者的主要方法，但该疗法的益处会因包括再灌注损伤在内的多种因素而减少。这种影响的确切机制尚未完全阐明。在这项研究中，我们确定了一种新的介质的缺血/再灌注（I/R）损伤的心脏中的ADIAPH 1。我们发现，Diaph 1缺失调节转录因子，血清反应因子，导致心肌细胞钙转运蛋白的调制。我们发现，Diaph 1的缺失改善了小鼠心脏I/R后的收缩功能，使DIAPH 1成为治疗进展性心肌梗死的潜在连续治疗靶点。
The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2 + ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction. DIAPH1 is a key mediator of ischemia/reperfusion injury in the heart. Diaph1 deletion regulates the transcription factor, serum response factor, leading to modulation of calcium transporters in cardiomyocytes. The effects of Diaph1 deletion are associated with improved contractile function after short-term ischemia/reperfusion injury, making it a potential adjunctive therapeutic target for treatment of evolving myocardial infarction. Although reperfusion therapy, using thrombolytic agents, has become the mainstay for the treatment of patients with myocardial infarction, benefits of this therapy are reduced by multiple factors including reperfusion injury. The precise mechanisms for this effect are yet to be fully delineated. In this study we identify the formin DIAPH1 as a novel mediator of ischemia/reperfusion (I/R) injury in the heart. We show that Diaph1 deletion regulates the transcription factor, serum response factor, leading to modulation of calcium transporters in cardiomyocytes. We show that deletion of Diaph1 improved contractile function after I/R in the mouse heart, making DIAPH1 a potential adjunctive therapeutic target for the treatment of evolving myocardial infarction.
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影响因子：
37.8
作者：
MILLER, TD;CHRISTIAN, TF;GIBBONS, RJ
通讯作者：
GIBBONS, RJ
影响因子：
37.8
作者：
PFEFFER, MA;BRAUNWALD, E
通讯作者：
BRAUNWALD, E
影响因子：
5
作者：
Kimura, Tomomi E.;Duggirala, Aparna;Hindmarch, Charles C. T.;Hewer, Richard C.;Cui, Mei-Zhen;Newby, Andrew C.;Bond, Mark
通讯作者：
Bond, Mark
DOI：
10.1152/ajpheart.00397.2003
发表时间：
2004-10-01
影响因子：
4.8
作者：
Bölck, B;Münch, G;Schwinger, RHG
通讯作者：
Schwinger, RHG
影响因子：
4.8
作者：
Mack, CP;Somlyo, AV;Owens, GK
通讯作者：
Owens, GK