Zinc-Mediated Inhibition of Soluble Epoxide Hydrolase Promotes Pulmonary Hypertension

<b>Rationale:</b> Pulmonary hypertension (PH) and vascular remodeling involve complex molecular mechanisms, with zinc and epoxyeicosatrienoic acids playing key roles. <b>Objectives:</b> We sought to investigate whether zinc-mediated inhibition of soluble epoxide hydrolase contributes to the development of PH and vascular remodeling under hypoxic conditions. <b>Methods:</b> Activity assays measured zinc-mediated soluble epoxide hydrolase inhibition, with mutagenesis and inductively coupled mass spectrometry identifying key cysteines. Pulmonary arteries and human pulmonary artery smooth muscle cells were used to measure vasoconstriction in response to epoxyeicosatrienoic acid, zinc, soluble epoxide hydrolase inhibition, or hypoxia treatment. A C230A knockin mouse was generated to elucidate the mechanism <i>in vivo</i> in acute and chronic hypoxia. Hydrolase expression was assessed in patients with idiopathic pulmonary artery hypertension or chronic obstructive pulmonary disease. Using UK Biobank data, soluble epoxide hydrolase mutations were assessed for a link to increased PH risk. <b>Measurements and Main Results:</b> Zinc inhibited soluble epoxide hydrolase by binding to C232/C230 and C423. C230A mice, resistant to zinc binding, were protected from acute hypoxia-induced soluble epoxide hydrolase inhibition, epoxyeicosatrienoic acid accumulation, and increased pulmonary pressure. C230A mice were also resistant to chronic hypoxia-induced PH and to the associated remodeling and loss of hydrolase expression. Patient lung samples showed decreased soluble epoxide hydrolase expression, echoing our findings with mice. UK Biobank participants with loss-of-function mutations in soluble epoxide hydrolase exhibited a higher risk of developing PH. <b>Conclusions:</b> Loss of soluble epoxide hydrolase activity, whether due to genetics, acute zinc-dependent inhibition, or chronic zinc-dependent loss of hydrolase protein, ultimately results in PH, and targeting this pathway may offer new therapeutic opportunities.