Lactate dehydrogenase-induced DNA Topoisomerase 1 is a novel regulator of smooth muscle cell proliferation and remodeling in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small pulmonary arteries (PAs), PA remodeling and unresolved increase of PA pressure. PA smooth muscle cells (PASMCs) in PAH undergo metabolic shift to glycolysis resulting in over-production of lactate, hyper-proliferation, and apoptosis resistance, but the mechanisms are not completely understood. By using lung tissues and pulmonary vascular cells from PAH and non-diseased human lungs, unbiased proteomics, network analysis, and gain-and-loss of function approaches, we here report that up-regulation of lactate dehydrogenase A (LDHA)-lactate axis promotes PASMC-specific over-lactylation and consequent over-accumulation of DNA topoisomerase 1 (TOP1) in small remodeled PAs from PAH lungs, leading to the up-regulation of Akt-mechanistic target of rapamycin 1 (mTORC1) signaling, hyper-proliferation, and reduced apoptosis. Smooth muscle-specific LDHA knockdown prevented, and Ldha inhibitor oxamate reversed SU5416/hypoxia-induced TOP1 accumulation, pulmonary vascular remodeling, and pulmonary hypertension (PH) in mice. Pharmacological inhibition of TOP1 with indotecan suppressed Akt-mTORC1, decreased proliferation, induced apoptosis in human PAH, but not control PASMCs, and reversed PA remodeling, PH, and RV dysfunction in rats. Collectively, these data provide a novel mechanistic link from LDHA-driven lactate over-production through lactylation and overaccumulation of TOP1, to the up-regulation of Akt-mTORC1, hyper-proliferation and apoptosis resistance of PASMCs, pulmonary vascular remodeling, and PH, and identify TOP1 as a new potentially attractive molecular target for the remodeling-focused therapeutic intervention. Take-home message: LDHA-lactate-induced over-lactylation and overaccumulation of Topoisomerase 1 (TOP1) promotes pulmonary artery smooth muscle cell hyper-proliferation, remodeling, and pulmonary arterial hypertension, which are reversed by TOP1 inhibitor indotecan.