Abstract 16968: Hypoxia-Lactate Dehydrogenase A-Lactate Axis Mediated Metabolic Adaptation of Macrophage Promotes Vascular Remodeling of Pulmonary Hypertension

Abstract

Introduction: Early recruitment of inflammatory macrophages with subsequent adaptation into pro-fibrotic phenotype have been reported essential for the development of PH. However, the underlying mechanism remains undetermined. Hypothesis: With enhanced glycolysis under hypoxic conditions, lactate dehydrogenase A(LDHA) mediated accumulation of lactate facilitates metabolic adaptation of macrophages and promotes the development of PH. Methods: Circulating monocytes, lactate, LDHA expression level were analyzed from patients with PH. The expression of LDHA, iNOS, and Arg1 in macrophages within lung tissue were examined on histopathology from patients with IPAH. Mice with myeloid specific knockout of Ldha were generated, and hemodynamic measurement, echocardiogram, histopathological examinations were conducted to evaluate pulmonary vascular remodeling using Su/Hx PH model. Bone marrow derived macrophage (BMDM) and vascular smooth muscle cells (SMCs) from mice were harvested for the mechanism study. Results: Lactate, monocytes and LDHA expression in PBMC were elevated in PH patients. On histopathology, perivascular macrophages infiltration with overexpression of LDHA, iNOS and Arg1 was noticed from lung tissue of IPAH patients, similar seen in both MCT-PH rats and Su/Hx mice. Mice with myeloid knockout of Ldha ( Ldha lyz2-/- ) shown decreased RVSP and improved right heart function on Echocardiogram. In vitro, inflammatory BMDM shown significantly elevated expression of LDHA and lactate under hypoxia, along with oversecreted growth factors including PDGF-β and promoting SMCs proliferation, which can be reversed by Ldha depletion. Conclusions: The hypoxia-LDHA-lactate axis plays a crucial role in metabolic adaption of macrophages under hypoxia condition, promoting SMCs proliferation and pulmonary vascular remodeling process. These findings suggest that targeting LDHA-lactate axis might exert therapeutic potential for PH.