Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul 120-752, Republic of Korea; Korea Testing & Research Institue (KTR), 155 Beodeunaru-ro, Yeongdeungpo-gu, Seoul 150-038, Republic of Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
Biomaterials. 2014 Aug;35(26):7562-73. doi: 10.1016/j.biomaterials.2014.05.025. Epub 2014 Jun 7.
Inflammatory response in myocardial ischemia-reperfusion injury plays a critical role in ventricular remodeling. To avoid deleterious effects of overwhelming inflammation, we blocked the expression of receptor for advanced glycation end-products (RAGE), a key mediator of the local and systemic inflammatory responses, via RNAi mechanism. Herein, a facial amphipathic deoxycholic acid-modified low molecular weight polyethylenimine (DA-PEI) was used as a siRNA delivery carrier to myocardium. The DA-PEI conjugate formed a stable complex with siRNA via electrostatic and hydrophobic interactions. The siRAGE/DA-PEI formulation having negligible toxicity could enhance intracellular delivery efficiency and successfully suppress RAGE expression both in vitro and in vivo. Furthermore, the cardiac administration of siRAGE/DA-PEI reduced apoptosis and inflammatory cytokine release, subsequently led to attenuation of left ventricular remodeling in rat myocardial infarction model. The potential therapeutic effects of RAGE gene silencing on myocardial ischemia-reperfusion injury may suggest that the siRAGE/DA-PEI delivery system can be considered as a promising strategy for treating myocardial infarction.
在心肌缺血再灌注损伤的炎症反应中，发挥了关键作用，在心室重构。为了避免有害的影响，势不可挡的炎症，我们阻止了表达的受体为晚期糖基化终产物（ RAGE ） ，一个关键调解人的局部和全身炎症反应，通过 RNAi 的机制。在此，面部两亲性去氧胆酸修饰的低分子量聚亚乙基亚胺（ DA - PEI ）被用作 siRNA 传递载体的心肌。该 DA - PEI 共轭形成一个稳定的复合物与 siRNA 通过静电和疏水相互作用。该 siRAGE / DA - PEI 制剂具有微不足道的毒性可以提高细胞内传递效率，并成功地抑制 RAGE 表达既在体外和体内。此外，心脏给药 siRAGE / DA - PEI 减少细胞凋亡和炎症细胞因子释放，随后导致衰减左心室重构大鼠心肌梗死模型。的潜在治疗效果的 RAGE 基因沉默对心肌缺血再灌注损伤可能表明， siRAGE / DA - PEI 传递系统可以被认为是一种很有前途的策略，用于治疗心肌梗死。
