Lan Qing, Chen Jian, Yang Yongqiang
Department of Cardiology, Deyang People's Hospital, Deyang, Sichuan, China.
Biotechnol Appl Biochem. 2025 Apr;72(2):460-468. doi: 10.1002/bab.2676. Epub 2024 Oct 2.
Free fatty acids (FFAs) have emerged as significant risk factors for atherosclerosis (AS). Prolonged exposure to FFAs induces vascular endothelial injury, including inflammatory responses and oxidative stress, which are central events in AS. Chromofungin (CHR), a peptide derived from chromogranin A (CGA), has been implicated in various biological functions. However, its physiological roles in endothelial biology and its involvement in the pathological development of AS have not been previously reported. In the present study, we investigated the underlying mechanisms through which CHR exerts its beneficial effects on FFA-challenged human aortic endothelial cells (HAECs). We found that treatment with CHR ameliorated the FFA-induced reduction in cell viability and increase in lactate dehydrogenase (LDH) release. Additionally, CHR mitigated oxidative stress by reducing mitochondrial reactive oxygen species (ROS) levels and increasing superoxide dismutase (SOD) activity. Furthermore, exposure to FFAs increased NADPH oxidase (NOX) 4 expression at both the mRNA and protein levels, which were attenuated by CHR in a dose-dependent manner. Notably, CHR reduced the levels of nucleotide-binding domain and leucine-rich repeat-containing (NLR) family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1 (p10), key components of the NLRP3 inflammasome complex, as well as interleukin 1β (IL-1β) and interleukin-18 (IL-18) expression. Mechanistically, it was demonstrated that FFAs reduced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which were rescued by CHR in a dose-dependent manner. Conversely, inhibition of AMPK with its specific inhibitor compound C abolished the protective effects of CHR against FFA-induced activation of the NLRP3 inflammasome in HAECs. Based on these findings, we conclude that CHR may serve as a promising agent for maintaining normal endothelial cell function and treating AS.
游离脂肪酸（FFAs）已成为动脉粥样硬化（AS）的重要危险因素。长期暴露于游离脂肪酸会导致血管内皮损伤，包括炎症反应和氧化应激，而这些都是动脉粥样硬化的核心事件。嗜铬素（CHR）是一种源自嗜铬粒蛋白A（CGA）的肽，具有多种生物学功能。然而，其在内皮生物学中的生理作用及其在动脉粥样硬化病理发展中的参与情况此前尚未见报道。在本研究中，我们探讨了CHR对游离脂肪酸刺激的人主动脉内皮细胞（HAECs）发挥有益作用的潜在机制。我们发现，用CHR处理可改善游离脂肪酸诱导的细胞活力降低和乳酸脱氢酶（LDH）释放增加的情况。此外，CHR通过降低线粒体活性氧（ROS）水平和增加超氧化物歧化酶（SOD）活性来减轻氧化应激。此外，暴露于游离脂肪酸会使NADPH氧化酶（NOX）4在mRNA和蛋白质水平的表达增加，而CHR以剂量依赖性方式减弱了这种增加。值得注意的是，CHR降低了含核苷酸结合结构域和富含亮氨酸重复序列（NLR）家族含pyrin结构域的3（NLRP3）、含凋亡相关斑点样蛋白的CARD（ASC）以及裂解的半胱天冬酶-1（p10）的水平，这些都是NLRP3炎性小体复合物的关键成分，同时也降低了白细胞介素1β（IL-1β）和白细胞介素-18（IL-18）的表达。从机制上来说，已证明游离脂肪酸会降低AMP激活的蛋白激酶（AMPK）和乙酰辅酶A羧化酶（ACC）的磷酸化，而CHR以剂量依赖性方式挽救了这种情况。相反，用其特异性抑制剂化合物C抑制AMPK消除了CHR对游离脂肪酸诱导的HAECs中NLRP3炎性小体激活的保护作用。基于这些发现，我们得出结论，CHR可能是维持正常内皮细胞功能和治疗动脉粥样硬化的有前景的药物。
