Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
Mediators Inflamm. 2023 Oct 4;2023:6112301. doi: 10.1155/2023/6112301. eCollection 2023.
Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-B/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.
持续的氧化应激和炎症会导致平滑肌细胞（SMC）增殖和迁移，这是血管增殖性疾病的特征。氧化修饰的低密度脂蛋白（OxLDL）会升高氧化应激水平、炎症反应和基质金属蛋白酶（MMP）的激活，最终导致 SMC 的迁移、增殖和表型改变。还原诱导富含半胱氨酸的 Kazal 基序蛋白（RECK）是一种膜锚定的 MMP 抑制剂。恩格列净是一种 SGLT2 抑制剂，具有多种心血管保护作用，包括抗氧化和抗炎作用。在这里，我们研究了：（i）OxLDL 是否调节 RECK 的表达；（ii）外源性表达 RECK 是否逆转 OxLDL 诱导的 SMC 迁移和增殖；（iii）恩格列净预处理是否逆转 OxLDL 诱导的 RECK 抑制、MMP 激活以及 SMC 迁移、增殖和分化。事实上，结果表明，在病理生理浓度下，OxLDL 通过 NF-B/miR-30b 依赖性 RECK 抑制促进 SMC 的迁移和增殖。此外，OxLDL 改变了 SMC 的表型，使其向更具炎症表型的方向发展，而过表达 RECK 则减弱了这种作用。此外，恩格列净治疗可逆转 OxLDL 诱导的 miR-30b 诱导、RECK 抑制、MMP 激活、SMC 迁移、增殖和促炎表型变化。OxLDL 诱导的心营养素（CT）-1 表达及其刺激的 SMC 增殖和迁移部分通过白血病抑制因子受体（LIFR）和糖蛋白 130（gp130）发挥作用。RECK 的异位表达通过与 LIFR 和 gp130 物理结合抑制了这些作用，这一点通过免疫沉淀/免疫印迹和双免疫荧光证实。重要的是，恩格列净抑制了 CT-1 诱导的有丝分裂和迁移作用。综上所述，这些结果表明维持 RECK 表达或恩格列净在以 SMC 增殖和迁移为特征的血管疾病中的治疗潜力。
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