Grobs Yann, Romanet Charlotte, Lemay Sarah-Eve, Bourgeois Alice, Voisine Pierre, Theberge Charlie, Sauvaget Melanie, Breuils-Bonnet Sandra, Martineau Sandra, El Kabbout Reem, Valasarajan Chanil, Chelladurai Prakash, Pelletier Andreanne, Mougin Manon, Dumais Elizabeth, Perron Jean, Flamand Nicolas, Potus François, Provencher Steeve, Pullamsetti Soni Savai, Boucherat Olivier, Bonnet Sebastien
Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Centre, Québec City, QC G1V 4G5, Canada.
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.
Sci Transl Med. 2024 Dec 11;16(777):eado7824. doi: 10.1126/scitranslmed.ado7824.
ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)-dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention.
ATP柠檬酸裂解酶（ACLY）是从头合成脂质和组蛋白乙酰化过程中的一种关键酶，在调节血管平滑肌细胞（VSMC）增殖和存活中起关键作用。我们发现，在冠状动脉疾病和肺动脉高压的血管重塑过程中，人冠状动脉和肺动脉组织中的ACLY表达上调。对从冠心病患者冠状动脉和肺动脉高压患者远端肺动脉分离的人原代培养VSMC进行ACLY的药理学和基因抑制，导致细胞增殖和迁移减少，对凋亡的易感性增加。这些细胞变化与糖酵解减少、脂质合成减少、一般控制非抑制蛋白5（GCN5）依赖性组蛋白乙酰化受损以及转录因子FOXM1的抑制有关。使用药理学抑制剂和VSMC特异性敲除小鼠的体内研究表明，ACLY抑制可减轻血管重塑。ACLY抑制减轻了啮齿动物颈动脉损伤和结扎模型中的重塑，并减轻了Sugen/低氧大鼠和小鼠模型中的肺动脉高压。此外，ACLY抑制在人离体模型中显示出血管重塑的改善，这些模型包括培养的人冠状动脉和隐静脉环以及精密切割的肺切片。我们的结果表明ACLY是治疗复杂血管疾病的一个新的治疗靶点，为未来的临床干预提供了有希望的途径。
