Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats

Abstract

We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4 wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8-12 wk). Briefly, inhibition of SEH was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of SEH induced a delayed increase in renal 5-HETE at 24 wk, in contrast to a decrease at 2 wk. Inhibition of SEH in female SHR from 8 to 12 wk did not reduce BP but caused profound decreases in renal 15(S)-HETrE, LTB4, TBX2, 5-HETE, and 20-HETE and increases in TriHOMEs. In male SHR, BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and SEH activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal SEH inhibition in female SHR cannot be simply explained by persistent reduction in renal SEH activity but rather by more complex and temporally dynamic interactions between the renal SEH, lipoxygenase, and cyclooxygenase pathways.

Prenatal dexamethasone-induced programmed hypertension and renal programming

“…sEH can metabolize EETs into DHETs. Previous studies have shown increased levels of sEH and 14,15-DHET in hypertension [22][23][24]. Therefore, our results suggest that programmed hypertension induced by DEX is, at least in part, attributable to sEH and the arachidonic acid pathway.…”

“…2A). Given that Ephx2 was identified as a significant DEG (16 week: Log 2 FC = 4.07) and is involved in the development of hypertension [24], we next analyzed soluble epoxide hydrolase (sEH, encoding Ephx2 gene) protein level and its activity in the 16-week-old kidney. We found that sEH protein level was higher in the DEX group compared to the control group (Fig.…”

Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

“…Although the same trends are seen in plasma and cortex, it is worth mentioning that the EETs/DHETEs ratio is much higher in kidney cortex than in plasma because DHETEs are predominantly located in plasma due to their higher polarity whereas EETs are largely located in the tissue. Inhibition of sEH has been shown to lower blood pressure in SHR [23,24]; however, t-AUCB did not lower blood pressure in diabetic SHR. Our data are consistent with the previously published data of Olearczyk et al [25], who showed that sEH inhibition had no effect on mean arterial pressure nor on blood glucose levels in hypertensive Goto-Kakizaki rats, as well as with our recent findings where knocking out of the sEH gene did not lower blood pressure or blood glucose in streptozotocin-induced diabetic mice [9].…”

Long-Term Follow-Up of Intrauterine Growth Restriction: Cardiovascular Disorders

“…For example, supplementation with vitamin C, vitamin E and NO has been shown to reduce blood pressure and prevent proteinuria in rats [109]. On the other hand, inhibition of certain factors can also improve cardiovascular health as well, as shown for NF-κB inhibitor pyrrolidine dithiocarbamate and soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid, which significantly reduce blood pressure in perinatal treated offspring of spontaneously hypertensive rats [110,111]. It has also been shown that IUGR fetal programming induced by a low-protein diet in rats can be reversed or even prevented by co-treatments with urea, which normalized body weight, or with glycine, which prevented an increase in blood pressure [112].…”