3-Bromopyruvate Attenuates Experimental Pulmonary Hypertension via Inhibition of Glycolysis

Abstract

BACKGROUND The shift of metabolism from mitochondrial oxidative phosphorylation to glycolysis and mitochondria binding partner of hexokinase are features common to cancer. These have been seen in pulmonary hypertension (PH) as well. An inhibitor of hexokinase 2 (HK 2), the small molecule 3-bromopyruvate (3-BrPA) is an incredibly powerful and swift-acting anticancer agent. However, whether it could be of potential benefit to PH has still been unknown. METHODS Sprague–Dawley rats with monocrotaline (MCT)-induced PH were administered 2 oral doses of 3-BrPA (15 and 30 mg/kg/day, respectively) for 14 days. Hemodynamic parameters were obtained by right heart catheterization. Histopathology, immunohistochemistry, transmission electron microscopy, flow cytometry, and assessments of relative protein expressions were conducted. RESULTS Compared with MCT treatment, 3-BrPA decreased mean pulmonary arterial pressure and pulmonary vascular resistance, and increased cardiac output. 3-BrPA significantly suppressed proliferation in addition to enhancing apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodeling and right ventricular hypertrophy. Treatment with 3-BrPA markedly reduced the mitochondrial membrane potential and restored mitochondrial structure. Furthermore, 3-BrPA significantly inhibited HK 2 expression but not HK 1. The expression of both pyruvate dehydrogenase kinase and lactate dehydrogenase was decreased whereas that of pyruvate dehydrogenase and cytosolic cytochrome c was upregulated with 3-BrPA administration. CONCLUSION This study demonstrates the reversal of PH by 3-BrPA is related to alteration in glycolysis and improved mitochondria function, indicating the “metabolic targeting” as a rational therapeutic strategy for PH.

Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension

“…Moreover, protein levels of key glycolytic enzymes PFKP and HKII were significantly higher in human PAH PAVSMC compared to controls ( Figures 2E–G ), and HIF1α over accumulation was detected in six out of seven PAVSMC from PAH patients compared to one out of five non-diseased (control) subjects ( Supplementary Figure 2 ). This is in good agreement with previously published data demonstrating the importance of glycolysis for PH ( 19 , 36 , 37 ). Together, our data demonstrate that glycolysis-metabolized glucose serves as a main source for increased de novo lipid synthesis in PAH PAVSMC, supporting a pro-proliferative cell phenotype.…”

RNA methylation, metabolic reprogramming and pulmonary hypertension

“…研究发现, MCT诱导的大鼠PH模型中HK2的表达 明显上升 [70] . 另有研究发现, 己糖激酶抑制剂(3-溴酰 丙酮酸)能够明显缓解MCT诱导的大鼠PH表型, 进一 步研究发现其是通过抑制糖酵解来发挥作用 [71] . 代谢 重编程关键基因PFKFB3在PH中的作用已经得到了广 泛的研究.…”

Metabolism, Mitochondrial Dysfunction, and Redox Homeostasis in Pulmonary Hypertension

“…Hexokinase, one of the limiting enzymes in the glycolytic pathway, has also been studied in PH. The upregulation of hexokinase, assessed via mRNA and protein expression, has been described in rat models of PH, and pharmacologic inhibition is associated with the amelioration of hemodynamic changes and SMC proliferation [ 22 , 23 ]. Increased levels of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a key enzyme for glucose oxidation, have been found in the pulmonary arteries of patients with PAH.…”