Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China; Department of Vascular Surgery, The First People's Hospital of Yibin, Yibin, 644000, China.
Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
Eur J Pharmacol. 2023 Nov 15;959:176084. doi: 10.1016/j.ejphar.2023.176084. Epub 2023 Oct 6.
Vascular calcification (VC) is associated with increased morbidity and mortality, especially among people with type 2 diabetes mellitus (T2DM). The pathogenesis of vascular calcification is incompletely understood, and until now, there have been no effective therapeutics for vascular calcification. The L-type calcium ion channel in the cell membrane is vital for Ca influx. The effect of L-type calcium ion channels on autophagy remains to be elucidated. Here, the natural compound thonningianin A (TA) was found to ameliorate vascular calcification in T2DM via the activation of L-type calcium ion channels. The results showed that TA had a concentration-dependent ability to decrease the transcriptional and translational expression of the calcification-related proteins runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2) and osteopontin (OPN) (P < 0.01) via ATG7-dependent autophagy in β-glycerophosphate (β-GP)- and high glucose (HG)-stimulated primary mouse aortic smooth muscle cells (MASMCs) and alleviate aortic vascular calcification in VitD3-stimulated T2DM mice. However, nifedipine, an inhibitor of L-type calcium ion channels, reversed TA-induced autophagy and Ca influx in MASMCs. Molecular docking analysis revealed that TA was located in the hydrophobic pocket of Cav1.2 α1C and was mainly composed of the residues Ile, Phe, Ala and Met, which confirmed the efficacy of TA in targeting the L-type calcium channel of Cav1.2 on the cell membrane. Moreover, in an in vivo model of vascular calcification in T2DM mice, nifedipine reversed the protective effects of TA on aortic calcification and the expression of the calcification-related proteins RUNX2, BMP2 and OPN (P < 0.01). Collectively, the present results reveal that the activation of cell membrane L-type calcium ion channels can induce autophagy and ameliorate vascular calcification in T2DM. Thonningianin A (TA) can target and act as a potent activator of L-type calcium ion channels. Thus, this research revealed a novel mechanism for autophagy induction via L-type calcium ion channels and provided a potential therapeutic for vascular calcification in T2DM.
血管钙化（VC）与发病率和死亡率的增加有关，尤其是在 2 型糖尿病患者（T2DM）中。血管钙化的发病机制尚不完全清楚，到目前为止，还没有有效的血管钙化治疗方法。细胞膜上的 L 型钙离子通道对于 Ca 内流至关重要。L 型钙离子通道对自噬的影响仍有待阐明。在这里，天然化合物通宁 A（TA）被发现通过激活 L 型钙离子通道来改善 T2DM 中的血管钙化。结果表明，TA 通过 ATG7 依赖性自噬，以浓度依赖性方式降低β-甘油磷酸（β-GP）和高葡萄糖（HG）刺激的原代小鼠主动脉平滑肌细胞（MASMCs）中钙化相关蛋白 runt 相关转录因子 2（RUNX2）、骨形态发生蛋白 2（BMP2）和骨桥蛋白（OPN）的转录和翻译表达（P < 0.01），并减轻 VitD3 刺激的 T2DM 小鼠主动脉血管钙化。然而，L 型钙离子通道抑制剂硝苯地平逆转了 TA 诱导的 MASMCs 中的自噬和 Ca 内流。分子对接分析表明，TA 位于 Cav1.2 α1C 的疏水性口袋中，主要由残基 Ile、Phe、Ala 和 Met 组成，这证实了 TA 靶向细胞膜上 Cav1.2 的 L 型钙离子通道的功效。此外，在 T2DM 小鼠血管钙化的体内模型中，硝苯地平逆转了 TA 对主动脉钙化和钙化相关蛋白 RUNX2、BMP2 和 OPN 表达的保护作用（P < 0.01）。总之，本研究结果揭示了细胞膜 L 型钙离子通道的激活可诱导自噬并改善 T2DM 中的血管钙化。通宁 A（TA）可以作为 L 型钙离子通道的靶标和有效激活剂。因此，本研究揭示了通过 L 型钙离子通道诱导自噬的新机制，并为 T2DM 中的血管钙化提供了一种潜在的治疗方法。
