Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
Cells. 2023 May 15;12(10):1394. doi: 10.3390/cells12101394.
Reperfusion after ischemia causes additional cellular damage, known as reperfusion injury, for which there is still no effective remedy. Poloxamer (P)188, a tri-block copolymer-based cell membrane stabilizer (CCMS), has been shown to provide protection against hypoxia/reoxygenation (HR) injury in various models by reducing membrane leakage and apoptosis and improving mitochondrial function. Interestingly, substituting one of its hydrophilic poly-ethylene oxide (PEO) blocks with a ()ert-butyl terminus added to the hydrophobic poly-propylene oxide (PPO) block yields a di-block compound (PEO-PPO) that interacts better with the cell membrane lipid bi-layer and exhibits greater cellular protection than the gold standard tri-block P188 (PEO-PPO-PEO). For this study, we custom-made three different new di-blocks (PEO-PPO, PEO-PPO and PEO-PPO) to systemically examine the effects of the length of each polymer block on cellular protection in comparison to P188. Cellular protection was assessed by cell viability, lactate dehydrogenase release, and uptake of FM1-43 in mouse artery endothelial cells (ECs) following HR injury. We found that di-block CCMS were able to provide the same or better EC protection than P188. Our study provides the first direct evidence that custom-made di-block CCMS can be superior to P188 in improving EC membrane protection, raising their potential in treating cardiac reperfusion injury.
缺血后再灌注会导致额外的细胞损伤，称为再灌注损伤，目前尚无有效的治疗方法。泊洛沙姆（P）188 是一种基于三嵌段共聚物的细胞膜稳定剂（CCMS），已被证明可通过减少膜渗漏和细胞凋亡并改善线粒体功能来防止各种模型中的缺氧/再氧合（HR）损伤。有趣的是，用疏水聚丙二醇（PPO）块中的一个亲水聚乙二醇（PEO）块取代一个伯丁基端，得到一个二嵌段化合物（PEO-PPO），它与细胞膜脂质双层的相互作用更好，并表现出比金标准三嵌段 P188（PEO-PPO-PEO）更好的细胞保护作用。在这项研究中，我们定制了三种不同的新型二嵌段（PEO-PPO、PEO-PPO 和 PEO-PPO），以系统地研究每个聚合物块的长度对 HR 损伤后与 P188 相比的细胞保护作用的影响。通过细胞活力、乳酸脱氢酶释放和 FM1-43 在小鼠动脉内皮细胞（EC）中的摄取来评估细胞保护作用。我们发现二嵌段 CCMS 能够提供与 P188 相同或更好的 EC 保护作用。我们的研究首次提供了直接证据，证明定制的二嵌段 CCMS 可以改善 EC 膜保护作用，优于 P188，这提高了它们在治疗心脏再灌注损伤方面的潜力。
