Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210029, Jiangsu Province, China.
Aging (Albany NY). 2022 Feb 3;14(3):1292-1306. doi: 10.18632/aging.203871.
The mechanisms of diabetes-related gastrointestinal dysmotility remains unclear. This study aimed to investigate the effect and mechanisms of proinflammatory adipokine visfatin (VF) in the contractile dysfunction of diabetic rat colonic smooth muscle. Twenty Sprague-Dawley rats were randomly divided into control and type 2 diabetes mellitus groups. VF levels in the serum and colonic muscle tissues were tested, the time of the bead ejection and contractility of colonic smooth muscle strips were measured, and the expression of ATP-sensitive potassium (K) channels in the colonic muscle tissues was analyzed. , we tested VF's effects on intracellular reactive oxygen species (ROS) levels, NF-κB's nuclear transcription, K channel expression, intracellular Ca concentrations, and myosin light chain (MLC) phosphorylation in colonic smooth muscle cells (CSMCs). The effects of NAC (ROS inhibitor) and BAY 11-7082 (NF-κB inhibitor) on K expression were also tested. Diabetic rats showed elevated VF levels in serum and colonic muscle tissues, a delayed distal colon ejection response time, weakened contractility of colonic smooth muscle strips, and increased K channel expression in colonic muscle tissues. VF significantly inhibited the contractility of colonic smooth muscle strips from normal rats. In cultured CSMCs, VF caused ROS overload, increased NF-κB nuclear transcription activity and increased expression of Kir6.1, eventually reducing intracellular Ca levels and MLC phosphorylation. NAC and BAY 11-7082 inhibited the VF-induced Kir6.1 upregulation. In conclusion, VF may cause contractile dysfunction of CSMCs by upregulating the expression of the Kir6.1 subunit of K channels via the ROS/NF-κB pathway and interfering with Ca signaling.
糖尿病相关胃肠动力障碍的机制尚不清楚。本研究旨在探讨促炎脂肪因子内脏脂肪素（VF）在糖尿病大鼠结肠平滑肌收缩功能障碍中的作用及机制。20 只 Sprague-Dawley 大鼠随机分为对照组和 2 型糖尿病组。检测血清和结肠肌组织中的 VF 水平，测量肠平滑肌条的射珠时间和收缩性，并分析结肠肌组织中 ATP 敏感性钾（K）通道的表达。然后，我们测试了 VF 对结肠平滑肌细胞（CSMC）内活性氧（ROS）水平、NF-κB 核转录、K 通道表达、细胞内 Ca 浓度和肌球蛋白轻链（MLC）磷酸化的影响。还测试了 NAC（ROS 抑制剂）和 BAY 11-7082（NF-κB 抑制剂）对 K 表达的影响。糖尿病大鼠血清和结肠肌组织中 VF 水平升高，远端结肠排空反应时间延迟，结肠平滑肌条收缩力减弱，结肠肌组织中 K 通道表达增加。VF 显著抑制正常大鼠结肠平滑肌条的收缩性。在培养的 CSMC 中，VF 导致 ROS 过载，增加 NF-κB 核转录活性和 Kir6.1 的表达，最终降低细胞内 Ca 浓度和 MLC 磷酸化。NAC 和 BAY 11-7082 抑制了 VF 诱导的 Kir6.1 上调。综上所述，VF 可能通过 ROS/NF-κB 通路上调 K 通道的 Kir6.1 亚基表达，并干扰 Ca 信号，导致 CSMC 的收缩功能障碍。
