HMGB1 is mechanistically essential in the development of experimental pulmonary hypertension

Pulmonary hypertension (PH) is a mortal disease featuring pulmonary vascular constriction and remodeling, right heart failure, and eventual death. Several reports showed that high-mobility group box 1 (HMGB1) appears to be critical for the development of PH; the underlying mechanism, however, has not been revealed. Experiments in the present study demonstrated that HMGB1 levels were elevated in the lung tissue and blood plasma of rats after chronic hypoxia exposure and monocrotaline treatment. HMGB1 was originally located within the nucleus and translocated to the cytoplasm of pulmonary artery smooth muscle cells (PASMCs) upon hypoxia exposure, a process that appeared to be mediated by endogenous H₂O₂. Exposure to HMGB1 mobilized calcium signaling in PASMCs, a response that was attenuated by extracellular Ca²⁺ removal, Toll-like receptor 4 (TLR4) inhibition by TAK-242, or transient receptor potential channel (TRPC) suppression with 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365. The sustained phosphorylation of the Akt pathway modulated HMGB1-induced migration of PASMCs. The blockage of HMGB1 with glycyrrhizin or anti-HMGB1 neutralizing antibody attenuated lung inflammation and PH establishment in rats after hypoxia exposure and monocrotaline treatment. The above findings reveal the mechanistic importance of HMGB1 in PH through TLR4- and TRPC-associated Ca²⁺ influx and Akt phosphorylation-driven PASMC migration.