PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
PFKFB3 in Smooth Muscle Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
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DOI：
10.1164/rccm.201812-2290oc
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发表时间：
2019-09-01
影响因子：
24.7
通讯作者：
Su, Yunchao
中科院分区：
文献类型：
--
作者：
Kovacs, Laszlo;Cao, Yapeng;Su, Yunchao
原理：糖酵解转变与肺动脉高压（PAH）的发病机制有关。目前尚不清楚糖酵解是如何增加的，以及糖酵解的增加如何促进肺血管重塑在PAH.Objectives：为了确定是否增加糖酵解是由6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）和PFKFB 3驱动的糖酵解如何诱导血管重塑在PAH.Methods：PFKFB 3水平测定肺动脉的患者和动物与PAH。评估PAH动物肺和肺动脉平滑肌细胞（PASMC）中的乳酸水平。遗传和药理学的方法被用来调查的作用PFKFB 3在PAH. Measures和主要结果：乳酸生产升高肺PAH啮齿动物和血小板源性生长因子治疗PASMCs。肺动脉高压患者和啮齿动物的肺动脉、肺动脉高压患者的PASMC以及血小板源性生长因子治疗的PASMC中的PFKFB 3蛋白含量较高。在PAH啮齿动物模型中，通过遗传破坏和化学抑制剂抑制PFKFB 3可减弱细胞外信号调节激酶（ERK 1/2）和钙蛋白酶-2的磷酸化/活化以及血管重塑，并减少血小板源性生长因子诱导的ERK 1/2和钙蛋白酶-2的磷酸化/活化、胶原合成和PASMC增殖。ERK 1/2抑制减弱钙蛋白酶-2的磷酸化/激活，以及Sugen/缺氧PAH大鼠的血管重塑，并减少乳酸诱导的钙蛋白酶-2的磷酸化/激活，胶原合成和PASMCs的增殖。Calpain-2抑制减少乳酸诱导的胶原合成和增殖的PASMCs.Conclusions：上调PFKFB 3介导的胶原合成和增殖的PASMCs，有助于在PAH的血管重塑。其机制是通过糖酵解和乳酸的升高，导致钙蛋白酶-2的ERK 1/2依赖性磷酸化激活钙蛋白酶。
Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.