Terawaki Yuichi, Nomiyama Takashi, Kawanami Takako, Hamaguchi Yuriko, Takahashi Hiroyuki, Tanaka Tomoko, Murase Kunitaka, Nagaishi Ryoko, Tanabe Makito, Yanase Toshihiko
Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
Cardiovasc Diabetol. 2014 Nov 19;13:154. doi: 10.1186/s12933-014-0154-3.
Recently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).
Six-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.
Linagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.
Linagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.
最近，基于胰高血糖素样肽-1（GLP-1）的疗法，包括二肽基肽酶-4（DPP-4）抑制剂和GLP-1受体激动剂，已成为最受欢迎的抗糖尿病疗法之一。此外，基于GLP-1的疗法不仅因其降血糖能力，还因其作为组织保护疗法的潜力而受到越来越多的关注。在本研究中，我们使用血管平滑肌细胞（VSMC）研究了DPP-4抑制剂利格列汀的血管保护作用。
将6周龄雄性C57BL/6小鼠分为对照组（n = 19）和利格列汀治疗组（3 mg/kg/天，n = 20）。在8周龄时诱导股动脉内皮剥脱损伤，然后在12周时评估新生内膜形成情况。为了评估大鼠主动脉平滑肌细胞的细胞增殖，进行了溴脱氧尿苷（BrdU）掺入试验。
与对照组相比，利格列汀治疗减少了血管损伤诱导的新生内膜形成（p <0.05）。在这些非糖尿病小鼠中，利格列汀治疗后体重和血糖水平没有变化。与对照组相比，利格列汀使血清活性GLP-1浓度增加了约1.5倍。此外，利格列汀治疗减轻了血管损伤诱导的氧化应激标志物尿8-羟基脱氧鸟苷（8-OHdG）的增加，尽管这种减轻没有统计学意义（p = 0.064）。此外，利格列汀没有改变血清基质细胞衍生因子-1α（SDF-1α）或血清血小板衍生生长因子（PDGF）的浓度。然而，利格列汀显著降低了体外VSMC增殖。
利格列汀可减轻血管损伤后的新生内膜形成和VSMC增殖，其作用超出了降血糖效果。
