Division of Cardiology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
Aging (Albany NY). 2022 Jun 13;14(11):4897-4913. doi: 10.18632/aging.204122.
Aging is a major risk factor for ischemic hypoxia-related diseases, including peripheral artery diseases (PADs). Signal transducer and activator of transcription 3 (STAT3) is a critical transcription activator in angiogenesis. Nevertheless, the effect of aging on endothelial cells and their responses to hypoxia are not well studied. Using a hindlimb hypoxic/ischemic model of aged mice, we found that aged mice (80-100-week-old) expressed significantly lower levels of angiogenesis than young mice (10-week-old). In our study, aged endothelial cells (≥30 passage) showed a significant accumulation of -galactosidase and a high expression of aging-associated genes, including p16, p21, and hTERT compared with young cells (<10 passage). After 24 hours of hypoxia exposure, proliferation, migration and tube formation were significantly impaired in aged cells compared with young cells. Notably, STAT3 and angiogenesis-associated proteins such as PI3K/AKT were significantly downregulated in aged mouse limb tissues and aged cells. Further, using STAT3 siRNA, we found that suppressing STAT3 expression in endothelial cells impaired proliferation, migration and tube formation under hypoxia. Correspondingly, in patients with limb ischemia we also observed a higher expression of circulating STAT3, associated with a lower rate of major adverse limb events (MALEs). Collectively, STAT3 could be a biomarker reflecting the development of MALE in patients and also a regulator of age-dependent angiogenesis post limb ischemia. Additional studies are required to elucidate the clinical applications of STAT3.
衰老是缺血缺氧相关疾病的一个主要危险因素，包括外周动脉疾病（PADs）。信号转导子和转录激活子 3（STAT3）是血管生成中的关键转录激活子。然而，衰老对内皮细胞及其对缺氧的反应的影响尚未得到很好的研究。使用老龄小鼠的后肢缺氧/缺血模型，我们发现老龄小鼠（80-100 周龄）的血管生成水平明显低于年轻小鼠（10 周龄）。在我们的研究中，与年轻细胞（<10 代）相比，老龄内皮细胞（≥30 代）表现出β-半乳糖苷酶的明显积累和衰老相关基因的高表达，包括 p16、p21 和 hTERT。在缺氧暴露 24 小时后，与年轻细胞相比，老龄细胞的增殖、迁移和管形成能力显著受损。值得注意的是，与年轻细胞相比，老龄小鼠肢体组织和细胞中的 STAT3 及与血管生成相关的蛋白，如 PI3K/AKT，表达明显下调。此外，通过使用 STAT3 siRNA，我们发现抑制内皮细胞中的 STAT3 表达会在缺氧下损害增殖、迁移和管形成。相应地，我们在肢体缺血患者中也观察到循环 STAT3 的表达较高，与主要不良肢体事件（MALEs）的发生率较低相关。总之，STAT3 可能是反映患者 MALEs 发展的生物标志物，也是肢体缺血后与年龄相关的血管生成的调节剂。需要进一步的研究来阐明 STAT3 的临床应用。
