3-Bromopyruvate alleviates the development of monocrotaline-induced rat pulmonary arterial hypertension by decreasing aerobic glycolysis, inducing apoptosis, and suppressing inflammation.

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PH) is a progressive disease with limited therapeutic options, ultimately leading to right heart failure and death. Recent findings indicate the role of the Warburg effect (aerobic glycolysis) in the development of PH. However, the effect of the glycolysis inhibitor 3-bromopyruvate (3-BrPA) on the pathogenesis of PH has not been well investigated. This study aimed to determine whether 3-BrPA inhibits PH and its possible mechanism. METHODS: PH was induced in adult Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline (MCT). 3-BrPA, or phosphate-buffered saline (PBS) was administered via intraperitoneal injection every other day from the first day of MCT-injection to 4 weeks of follow-up, and indices such as right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary arteriolar remodeling indicated by percent media thickness (% MT), lactate levels and glucose consumption, were evaluated. Pulmonary arteriolar remodeling and right ventricular hypertrophy were observed in hematoxylin-eosin-stained lung sections. Western blotting, immunohistochemistry, and/or immunofluorescence analyses were used to measure the expression of relevant proteins. A cytochrome C release apoptosis assay and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining were used to measure cell apoptosis. RESULTS: MCT-induced PH showed a significant increase in glucose consumption (0 vs. 4 weeks 0.87 ±â€Š0.23 vs. 2.94 ±â€Š0.47, P = 0.0042) and lactate production (0 vs. 4 weeks 4.19 ±â€Š0.34 vs. 8.06 ±â€Š0.67, P = 0.0004). Treatment with 3-BrPA resulted in a concomitant reduction in glucose consumption (1.10 ±â€Š0.35 vs. 3.25 ±â€Š0.47, P = 0.0063), lactate production (5.09 ±â€Š0.55 vs. 8.06 ±â€Š0.67, P = 0.0065), MCT-induced increase in RVSP (39.70 ±â€Š2.94 vs. 58.85 ±â€Š2.32, P = 0.0004), pulmonary vascular remodeling (% MT, 43.45% ±â€Š1.41% vs. 63.66% ±â€Š1.78%, P < 0.0001), and right ventricular hypertrophy (RVHI, 38.57% ±â€Š2.69% vs. 62.61% ±â€Š1.57%, P < 0.0001) when compared with those of the PBS-treated group. 3-BrPA, a hexokinase 2 inhibitor, exerted its beneficial effect on PH by decreasing aerobic glycolysis and was also associated with inhibiting the expression of glucose transporter protein-1, inducing apoptosis, and suppressing inflammation. CONCLUSIONS: 3-BrPA might have a potential beneficial effect on the PH treatment.