Tissue engineering with targeted delivery of nanotized S-nitrosyl mutant of NEMO ameliorates myocardial infarction.

Nanomedicine (London, England) Pub Date : 2025-05-01 Epub Date: 2025-04-16 DOI:10.1080/17435889.2025.2491989

Abhik Kar, Soumyadeep Gupta, Arkapravo Matilal, Sagartirtha Sarkar

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Abstract

Background: Myocardial infarction (MI) is characterized by an elevated nitrosative and hypoxic microenvironment due to reduced coronary blood flow. NEMO (IKKγ) regulates the formation of the IKK holo-complex to activate NFκB-p65 signaling. This study reports successful restoration of MI through cardiomyocyte-targeted nanotized S-nitrosyl mutant of NEMO under elevated nitrosative stress.

Methods: The MI model was generated in male Wistar rats. S-nitrosyl mutant of NEMO (R- NEMO) was selectively delivered to the cardiomyocytes via targeted chitosan nano-vehicle.

Results: Nano-conjugated R- NEMO delivery to diseased cardiomyocytes resulted in downregulation of nitrosative stress and cellular apoptosis leading to regressed infarct area with improved cardiac pathophysiology. Mechanistically, NEMO-p300 binding in R- NEMO expressed cells destabilized p65-p300 complex leading to regressed nitrosative stress and cellular apoptosis. The NEMO mutant inhibits the PGC1α-p65 complex-mediated degradation of PGC1α, leading to upregulation of VEGF. A shift in the binding preference of p65 from PGC1α/p300 to HDAC1 results in the downregulation of the cell-cycle inhibitor and the induction of cell-cycle re-entry markers during MI.

Conclusion: Tissue-targeted R- NEMO nanoconjugates show potential to ameliorate MI insult by downregulating apoptosis and promoting the proliferative prowess of the resident cardiomyocytes with potential revascularization at infarct sites; thus, repairing the damaged myocardium.

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组织工程靶向递送纳米s -亚硝基NEMO突变体可改善心肌梗死。

背景：心肌梗死（MI）的特征是由于冠状动脉血流量减少导致亚硝化和缺氧微环境升高。NEMO （IKKγ）调节IKK holo复合物的形成以激活NFκB-p65信号。本研究报道了在高亚硝化应激下，通过心肌细胞靶向纳米s -亚硝基NEMO突变体成功恢复心肌梗死。方法：建立雄性Wistar大鼠心肌梗死模型。通过靶向壳聚糖纳米载体选择性地将NEMO s -亚硝基突变体（R- NEMO）递送至心肌细胞。结果：纳米修饰的R- NEMO递送到病变心肌细胞，导致亚硝化应激和细胞凋亡下调，导致梗死面积消退，心脏病理生理改善。从机制上讲，NEMO-p300结合R- NEMO表达的细胞破坏了p65-p300复合物的稳定性，导致亚硝化应激和细胞凋亡的逆转。NEMO突变体抑制PGC1α-p65复合物介导的PGC1α降解，导致VEGF上调。p65的结合偏好从PGC1α/p300转变为HDAC1，导致心肌梗死期间细胞周期抑制剂的下调和细胞周期再进入标记物的诱导。结论：组织靶向R- NEMO纳米偶联物通过下调细胞凋亡和促进梗死部位心肌细胞的增殖能力来改善心肌梗死的损害；因此，修复受损的心肌。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Nanomedicine (London, England)

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