Department of Pharmacology New York Medical College Valhalla NY USA.
Department of Medicine, Division of Pediatric Cardiology, Physiology New York Medical College Valhalla NY USA.
J Am Heart Assoc. 2024 Oct;13(19):e035174. doi: 10.1161/JAHA.123.035174. Epub 2024 Sep 18.
G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer.
CRISPR-Cas9 genome editing was used to generate the variant (N126D; ) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PD+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca were increased in the lungs of G6PD+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PD+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7.
Our results suggest G6PD increases inositol triphosphate-Ca signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.
G6PD（葡萄糖-6-磷酸脱氢酶）是糖酵解途径中的关键酶，与癌症的发病机制和肺动脉高压相关的血管重塑有关。在这里，我们研究了一种 X 连锁突变（N126D 多态性）的作用，已知这种突变会增加来自撒哈拉以南非洲和许多具有非洲血统的个体患心血管疾病的风险，该突变与用于治疗癌症的血管内皮细胞生长因子受体阻滞剂诱导的肺动脉高压发病机制有关。
使用 CRISPR-Cas9 基因组编辑技术在大鼠中产生该变异（N126D； ）。单次皮下注射血管内皮细胞生长因子受体阻滞剂 sugen-5416（SU；20mg/kg 在 DMSO 中），目前正在进行用于癌症治疗的 2/3 期临床试验，将其注射到大鼠及其野生型同窝仔鼠中。在 8 周的常氧条件下，评估右心室压力和肥厚、肺动脉重塑、代谢谱和细胞因子表达。G6PD+SU/常氧大鼠的右心室压力和肺动脉壁厚度增加。同时，G6PD+SU/常氧大鼠的肺部氧化型谷胱甘肽、三磷酸肌醇和细胞内 Ca 水平升高，而一氧化氮水平降低。G6PD+SU/常氧大鼠的肺部纤溶酶原激活物抑制剂-1、凝血酶-抗凝血酶复合物和促炎细胞因子 CCL3（趋化因子[C-C 基序]配体）、CCL5 和 CCL7 的表达也增加。
我们的结果表明，G6PD 增加了 SU 处理大鼠中的三磷酸肌醇-Ca 信号、炎症、血栓形成和肥厚性肺动脉重塑。这表明携带这种 G6PD 变异的患者使用血管内皮细胞生长因子受体阻滞剂后发生肺动脉高压的风险增加。
