MMP-9 responsive hydrogel promotes diabetic wound healing by suppressing ferroptosis of endothelial cells

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL Bioactive Materials Pub Date : 2024-09-24 DOI:10.1016/j.bioactmat.2024.09.006

Chuanlu Lin , Yiqiang Hu , Ze Lin , Longyu Du , Yixin Hu , Lizhi Ouyang , Xudong Xie , Peng Cheng , Jiewen Liao , Li Lu , Ruiyin Zeng , Ping Xia , Zhiyong Hou , Guohui Liu , Hankun Hu

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Abstract

Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca²⁺ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.

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MMP-9 反应性水凝胶通过抑制内皮细胞的铁突变促进糖尿病伤口愈合

铁蛋白沉积在糖尿病伤口的进展中起着至关重要的作用，这表明针对铁蛋白沉积的治疗策略具有潜力。瞬时受体电位蛋白1（TRPA1）是一种非选择性钙通道，可作为各种物理或化学刺激的受体。肉桂醛（CA）是一种特异性 TRPA1 激动剂。在体外实验中，我们观察到高葡萄糖（HG）处理会诱导内皮细胞铁凋亡，从而损害细胞功能。CA 成功地抑制了内皮细胞的铁突变，改善了迁移、增殖和管形成。进一步的机理研究表明，CA激活TRPA1诱导的Ca2+流入促进了钙调素依赖性蛋白激酶II（CaMKII）的磷酸化和核因子-E 2相关因子2（Nrf2）的转位，这有助于谷胱甘肽过氧化物酶4（GPX4）的升高，从而抑制了内皮细胞的嗜铁性。此外，CA还被纳入了MMP-9反应性可注射双相杂交水凝胶（CA@HA-Gel）中，使其能以炎症反应的方式在糖尿病伤口中高效持续释放。结果表明，CA@HA-Gel 能抑制伤口内皮细胞铁蛋白沉积，显著促进糖尿病伤口愈合。总之，本研究的结果强调了 CA@HA-Gel 在治疗与铁嗜酸相关疾病方面的潜在治疗应用。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.