Abstract：
OBJECTIVE: Polydopamine nanoparticles (PDA NPs) are a promising topic in the fields of drug delivery, tissue engineering, bioimaging, etc. The present study aims to explore the impact of PDA NPs carrying ferroptosis inhibitor ferstatin-1 (Fer-1) on myocardial ischemia-reperfusion injury (MIRI).
METHODS: After establishment of a rat model of MIRI and PDA NPs, the rats were divided into 4 groups: model group, sham operation group, Fer-1 group, and nano+Fer-1 group (n=8). To detect the effect of PDA NPs encapsulating Fer-1 on ferroptosis in MIRI rats, we further set up NOX4 overexpression group (pc-NOX4 group), NOX4 inhibitor group (Fulvene-5 group), nano+Fer-1+pc-NOX4 group, and nano+Fer-1+Fulvene-5 group (n=8). A CCK-8 assay was conducted to assess cell viability and staining to detect cardiomyocyte apoptosis and observe myocardial infraction.
RESULTS: PDA NPs loaded with Fer-1 were successfully prepared with good safety and biocompatibility. Administration of PDA NPs carrying Fer-1 notably alleviated myocardial injury and hindered the process of ferroptosis in MIRI rats when inducing downregulation of NOX4 expression. Additionally, overexpression of GPX4 significantly attenuated myocardial injury in MIRI rats. While Fer-1 was shown to inhibit the expression of NOX4, the NOX4 inhibitor Fulvene-5 greatly elevated GPX4 and FTH1 expression in cardiomyocytes, and down-regulated the content of Fe2+, especially in the nanometer+Fer-1+Fulvene-5 group.
CONCLUSIONS: With promising safety and biocompatibility, PDA NPs encapsulated Fer-1 decrease GPX4 and FTH1 expression by inhibiting the level of NOX4 in myocardial cells of MIRI rats, thereby suppressing ferroptosis of cardiomyocytes and alleviating myocardial injury.
METHODS: After establishment of a rat model of MIRI and PDA NPs, the rats were divided into 4 groups: model group, sham operation group, Fer-1 group, and nano+Fer-1 group (n=8). To detect the effect of PDA NPs encapsulating Fer-1 on ferroptosis in MIRI rats, we further set up NOX4 overexpression group (pc-NOX4 group), NOX4 inhibitor group (Fulvene-5 group), nano+Fer-1+pc-NOX4 group, and nano+Fer-1+Fulvene-5 group (n=8). A CCK-8 assay was conducted to assess cell viability and staining to detect cardiomyocyte apoptosis and observe myocardial infraction.
RESULTS: PDA NPs loaded with Fer-1 were successfully prepared with good safety and biocompatibility. Administration of PDA NPs carrying Fer-1 notably alleviated myocardial injury and hindered the process of ferroptosis in MIRI rats when inducing downregulation of NOX4 expression. Additionally, overexpression of GPX4 significantly attenuated myocardial injury in MIRI rats. While Fer-1 was shown to inhibit the expression of NOX4, the NOX4 inhibitor Fulvene-5 greatly elevated GPX4 and FTH1 expression in cardiomyocytes, and down-regulated the content of Fe2+, especially in the nanometer+Fer-1+Fulvene-5 group.
CONCLUSIONS: With promising safety and biocompatibility, PDA NPs encapsulated Fer-1 decrease GPX4 and FTH1 expression by inhibiting the level of NOX4 in myocardial cells of MIRI rats, thereby suppressing ferroptosis of cardiomyocytes and alleviating myocardial injury.
摘要：
目的：聚多巴胺纳米颗粒（PDANP）是药物递送领域的一个有前途的课题，组织工程,生物成像,等。本研究旨在探讨携带铁凋亡抑制剂Ferstatin-1（Fer-1）的PDANPs对心肌缺血再灌注损伤（MIRI）的影响。
方法：建立大鼠MIRI和PDANP模型后，将大鼠分为4组:模型组,假手术组,Fer-1组,和nano+Fer-1组(n=8)。为了检测封装Fer-1的PDANPs对MIRI大鼠铁凋亡的影响，我们进一步建立了NOX4过表达组（pc-NOX4组），NOX4抑制剂组（Fulvene-5组），nano+Fer-1+pc-NOX4组，nano+Fer-1+Fulvene-5组(n=8)。进行CCK-8测定以评估细胞活力和染色以检测心肌细胞凋亡并观察心肌梗死。
结果：成功制备了负载Fer-1的PDANP，具有良好的安全性和生物相容性。当诱导NOX4表达下调时，携带Fer-1的PDANP的给药明显减轻了MIRI大鼠的心肌损伤并阻碍了铁凋亡过程。此外,GPX4的过表达可显着减轻MIRI大鼠的心肌损伤。虽然显示Fer-1抑制NOX4的表达，但NOX4抑制剂Fulvene-5大大提高了心肌细胞中GPX4和FTH1的表达，并下调了Fe2+的含量，特别是在纳米+Fer-1+Fulvene-5组中。
结论：具有良好的安全性和生物相容性，Fer-1封装的PDANPs通过抑制MIRI大鼠心肌细胞中NOX4的水平降低GPX4和FTH1的表达，从而抑制心肌细胞的铁性凋亡，减轻心肌损伤。
方法：建立大鼠MIRI和PDANP模型后，将大鼠分为4组:模型组,假手术组,Fer-1组,和nano+Fer-1组(n=8)。为了检测封装Fer-1的PDANPs对MIRI大鼠铁凋亡的影响，我们进一步建立了NOX4过表达组（pc-NOX4组），NOX4抑制剂组（Fulvene-5组），nano+Fer-1+pc-NOX4组，nano+Fer-1+Fulvene-5组(n=8)。进行CCK-8测定以评估细胞活力和染色以检测心肌细胞凋亡并观察心肌梗死。
结果：成功制备了负载Fer-1的PDANP，具有良好的安全性和生物相容性。当诱导NOX4表达下调时，携带Fer-1的PDANP的给药明显减轻了MIRI大鼠的心肌损伤并阻碍了铁凋亡过程。此外,GPX4的过表达可显着减轻MIRI大鼠的心肌损伤。虽然显示Fer-1抑制NOX4的表达，但NOX4抑制剂Fulvene-5大大提高了心肌细胞中GPX4和FTH1的表达，并下调了Fe2+的含量，特别是在纳米+Fer-1+Fulvene-5组中。
结论：具有良好的安全性和生物相容性，Fer-1封装的PDANPs通过抑制MIRI大鼠心肌细胞中NOX4的水平降低GPX4和FTH1的表达，从而抑制心肌细胞的铁性凋亡，减轻心肌损伤。
