eNOS Uncoupling-ER Stress-Mitochondrial Dysfunction Axis in the Development of Pulmonary Hypertension.

Pulmonary hypertension (PH) was induced by 2,4-diamino 6-hydroxypyrimidine or hypoxia exposure. Remarkably, folic acid (attenuating endothelial nitric oxide synthase [eNOS] uncoupling) or phenylbutyric acid (abrogating endoplasmic reticulum stress) markedly alleviated mean pulmonary arterial pressure /right ventricular systolic pressure, vascular remodeling, total and mitochondrial superoxide production, and eNOS uncoupling, while preserving NO bioavailability. MitoTempo to scavenge mitochondrial reactive oxygen species abolished molecular and pathophysiological features of PH. Folic acid, phenylbutyric acid, or combination attenuated mitochondrial swelling and distortion of mitochondrial cristae. Using 2,4-diamino 6-hydroxypyrimidine increased total and mitochondrial superoxide production in pulmonary artery endothelial cells. Our data for the first time establish a novel eNOS uncoupling/endoplasmic reticulum stress/mitochondrial dysfunction signaling axis in mediating PH, which are targetable for novel therapeutics.