Figure 8.

Schematic diagram depicting a possible role of AK4 in promoting a glycolytic, pro-proliferative, and pro-survival phenotype of PASMCs. Hypoxia upregulates AK4 in an HIF-1α-dependent manner. AK4 upregulation leads to Akt activation and increases HIF-1α levels, possibly by increasing ROS, indicating the existence of an AK4-HIF-1α feedforward loop in hypoxic PASMCs. The AK4-HIF-1α axis gives rise to increased levels of glycolytic enzymes (HK2, LDHA, PDHK1), promotes a metabolic shift from OXPHOS towards glycolysis (glycolytic shift), and increases PASMC proliferation and viability. This abnormal phenotype of PASMCs is a hallmark of the pulmonary vascular remodeling in pulmonary hypertension. Thus, targeting AK4 may represent a new therapeutic strategy for PH.