Reciprocal Actions of Constrictor Prostanoids and Superoxide in Chronic Hypoxia-Induced Pulmonary Hypertension: Roles of EETs
Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by CYP/epoxygenase and metabolized by soluble epoxide hydrolase (sEH). Roles of EETs in hypoxia-induced pulmonary hypertension (HPH) remain elusive. The present study aimed to investigate the underlying mechanisms, by which EETs potentiate HPH. Experiments were conducted on sEH knockout (sEH-KO) and wild type (WT) mice after exposure to hypoxia (10% oxygen) for three weeks. In normal/normoxic conditions, WT and sEH-KO mice exhibited comparable pulmonary artery acceleration time (PAAT), ejection time (ET), PAAT/ET ratio, and velocity time integral (VTI), along with similar right ventricular systolic pressure (RVSP). Chronic hypoxia significantly reduced PAAT, ET, and VTI, coincided with an increase in RVSP; these impairments were more severe in sEH-KO than WT mice. Hypoxia elicited downregulation of sEH and upregulation of CYP2C9 accompanied with elevation of CYP-sourced superoxide, leading to enhanced pulmonary EETs in hypoxic mice with significantly higher levels in sEH-KO mice. Isometric tension of isolated pulmonary arteries was recorded. In addition to downregulation of eNOS-induced impairment of vasorelaxation to ACh, HPH mice displayed upregulation of thromboxane A2 (TXA2) receptor, paralleled with enhanced pulmonary vasocontraction to a TXA2 analog (U46619) in an sEH-KO predominant manner. Inhibition of COX-1 or COX-2 significantly prevented the enhancement by approximately 50% in both groups of vessels, and the remaining incremental components were eliminated by scavenging of superoxide with Tiron. In conclusion, hypoxia-driven increases in EETs, intensified COXs/TXA2 signaling, great superoxide sourced from activated CYP2C9, and impaired NO bioavailability work in concert, to potentiate HPH development.
Kandhi, S., Alruwaili, N., Wolin, M., Sun, D., & Huang, A. (2019). Reciprocal Actions of Constrictor Prostanoids and Superoxide in Chronic Hypoxia-Induced Pulmonary Hypertension: Roles of EETs. Pulmonary Circulation, 9 (4), 2045894019895947-2045894019895947. https://doi.org/10.1177/2045894019895947