Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan;1867(1):159062. doi: 10.1016/j.bbalip.2021.159062. Epub 2021 Oct 2.
Phospholipase D (PLD) generates the signaling lipid phosphatidic acid (PA) and has been known to mediate proliferation signal in vascular smooth muscle cells (VSMCs). However, it remains unclear how PLD contributes to vascular diseases. VSMC proliferation directly contributes to the development and progression of cardiovascular disease, such as atherosclerosis and restenosis after angioplasty. Using the mouse carotid artery ligation model, we find that deletion of Pld1 gene inhibits neointima formation of the injuried blood vessels. PLD1 deficiency reduces the proliferation of VSMCs in both injured artery and primary cultures through the inhibition of ERK1/2 and AKT signals. Immunohistochemical staining of injured artery and flow cytometry analysis of VSMCs shows a reduction of the levels of reactive oxygen species (ROS) in Pld1 VSMCs. An increase of intracellular ROS by hydrogen peroxide stimulation restored the reduced activities of ERK and AKT in Pld1 VSMCs, whereas a reduction of ROS by N-acetyl-l-cysteine (NAC) scavenger lowered their activity in wild-type VSMCs. These results indicate that PLD1 plays a critical role in neointima, and that PLD1 mediates VSMC proliferation signal through promoting the production of ROS. Therefore, inhibition of PLD1 may be used as a therapeutic approach to suppress neointimal formation in atherosclerosis and restenosis after angioplasty.
磷脂酶 D（PLD）生成信号脂质磷脂酸（PA），并被认为在血管平滑肌细胞（VSMCs）中介导增殖信号。然而，PLD 如何促进血管疾病仍然不清楚。VSMC 增殖直接导致心血管疾病的发展和进展，例如动脉粥样硬化和血管成形术后再狭窄。使用小鼠颈动脉结扎模型，我们发现 Pld1 基因缺失抑制损伤血管的新生内膜形成。PLD1 缺乏通过抑制 ERK1/2 和 AKT 信号减少损伤动脉和原代培养物中 VSMCs 的增殖。损伤动脉的免疫组织化学染色和 VSMCs 的流式细胞术分析表明，Pld1 VSMCs 中的活性氧（ROS）水平降低。过氧化氢刺激增加细胞内 ROS 水平可恢复 Pld1 VSMCs 中 ERK 和 AKT 活性的降低，而 N-乙酰-L-半胱氨酸（NAC）清除剂降低 ROS 水平可降低野生型 VSMCs 中的活性。这些结果表明，PLD1 在新生内膜中起关键作用，并且 PLD1 通过促进 ROS 的产生来介导 VSMC 增殖信号。因此，抑制 PLD1 可能被用作抑制动脉粥样硬化和血管成形术后再狭窄中新生内膜形成的治疗方法。
