Kim Daehoon, Shin Jieun, Choi Yeon-Kyung, Lee You Mie, Park Keun-Gyu, Kim Hyang Sook, Byun Jun-Kyu
Department of Biomedical Science, Kyungpook National University, Daegu, Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Korea.
Diabetes Metab J. 2025 Jul 30. doi: 10.4093/dmj.2024.0632.
Vascular smooth muscle cells (VSMCs) play a crucial role in the development of occlusive vascular diseases through abnormal proliferation and migration. This pathological behavior is closely associated with mitochondrial reactive oxygen species (ROS)-mediated mitochondrial DNA (mtDNA) damage. The mitochondrial carrier protein solute carrier family 25 member 33 (SLC25A33), essential for nucleoside transport, is integral to mtDNA production. This study aimed to investigate the effects of SLC25A33 inhibition on the proliferation and migration of VSMCs, as well as its impact on neointima formation.
VSMCs were isolated from the thoracic aorta of 4-week-old Sprague-Dawley rats. The effects of small interfering RNAinduced silencing of SLC25A33 mRNA on platelet-derived growth factor (PDGF)-induced proliferation and migration of VSMCs were analyzed. The in vivo effects of targeting the SLC25A33 gene on neointima formation were evaluated using a murine carotid artery ligation model by perivascularly applying Lenti-shSLC25A33 with Pluronic F-127 gel.
First, we observed an upregulation of the SLC25A33 protein in the carotid artery ligation-induced neointima in mice. Silencing of SLC25A33 suppressed the PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Knockdown of SLC25A33 inhibited PDGF-induced production of mtDNA and ROS, consequently inactivating the cyclic GMP-AMP synthesis (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-nuclear factor kappa B (NF-κB) pathway. Furthermore, the downregulation of SLC25A33 reduced carotid artery ligation-induced neointima in mice.
This study suggests that targeting SLC25A33 in VSMCs could be a novel therapeutic strategy to prevent occlusive vascular diseases.
血管平滑肌细胞（VSMCs）通过异常增殖和迁移在闭塞性血管疾病的发展中起关键作用。这种病理行为与线粒体活性氧（ROS）介导的线粒体DNA（mtDNA）损伤密切相关。线粒体载体蛋白溶质载体家族25成员33（SLC25A33）对核苷转运至关重要，是mtDNA产生所必需的。本研究旨在探讨抑制SLC25A33对VSMCs增殖和迁移的影响及其对新生内膜形成的影响。
从4周龄Sprague-Dawley大鼠的胸主动脉中分离VSMCs。分析小干扰RNA诱导沉默SLC25A33 mRNA对血小板衍生生长因子（PDGF）诱导的VSMCs增殖和迁移的影响。通过血管周围应用携带Lenti-shSLC25A33的普朗尼克F-127凝胶，利用小鼠颈动脉结扎模型评估靶向SLC25A33基因对新生内膜形成的体内影响。
首先，我们观察到小鼠颈动脉结扎诱导的新生内膜中SLC25A33蛋白上调。沉默SLC25A33可抑制PDGF刺激的VSMCs增殖、迁移和细胞周期进程。敲低SLC25A33可抑制PDGF诱导的mtDNA和ROS产生，从而使环磷酸鸟苷-腺苷合成酶（cGAS）-干扰素基因刺激因子（STING）-TANK结合激酶1（TBK1）-核因子κB（NF-κB）通路失活。此外，SLC25A33的下调减少了小鼠颈动脉结扎诱导的新生内膜。
本研究表明，靶向VSMCs中的SLC25A33可能是预防闭塞性血管疾病的一种新的治疗策略。
