Lactate dehydrogenase a in pulmonary arterial hypertension: From metabolic reprogramming to therapeutic targeting

Pulmonary arterial hypertension (PAH) is a progressive vascular disease marked by increased pulmonary arterial pressure leading to right ventricular overload and heart failure. Its pathogenesis involves vascular remodeling, characterized by an imbalance of vasoactive mediators, excessive endothelial and smooth muscle proliferation, and resistance to apoptosis. In the past decade, research has highlighted metabolic reprogramming, particularly aerobic glycolysis, as a central feature of PAH. This shift increases lactate concentration in the pulmonary artery (PA) as a byproduct of anaerobic glycolysis, largely influenced by lactate dehydrogenase A (LDH-A). LDH-A plays a pivotal role in vascular remodeling by regenerating nicotinamide adenine dinucleotide (NAD + ) to sustain glycolytic flux and drive pathological processes, including smooth muscle proliferation, endothelial dysfunction, and epigenetic modifications. LDH-A activates the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, a key regulator of cell growth, and induces hypoxia-inducible factor 1α (HIF 1α), which promotes endothelial to mesenchymal transition. Moreover, LDH-A enhances lactylation, an epigenetic modification that further stimulates cell proliferation. Given these mechanisms, LDH-A is considered a crucial factor in the progression of PAH. Its inhibition may represent a promising therapeutic target, with potential to reduce vascular remodeling and improve right ventricular function. Despite this, studies exploring LDH-A’s role in PAH remain limited, underscoring the need for further research to clarify its therapeutic potential.