Abstract P286: Circulating Lipoxin A4 Causes Resolution of Inflammation via Estrogen Receptor Activation, While Mitochondria N-Formyl Peptides Induce Inflammation via Formyl Peptide Receptor in Hypertension

Abstract

Recently, we observed that mitochondrial components have inflammatogenic proprieties and that their fragments are elevated in the circulation of spontaneously hypertensive rats (SHR). Also, infusion of mitochondrial N-formyl peptides (F-MITs) into rats induces inflammation and vascular dysfunction via formyl peptide receptor (FPR) activation. In contrast, Lipoxin A4 (LXA4), a mediator of resolution of inflammation, also binds FPR. However, LXA4-FPR-dependent effects seem to be opposite from F-MITs. We first hypothesized that LXA4 is decreased in SHR. We collected plasma from male SHR and Wistar Kyoto rats (WKY) (12 weeks old) and LXA4 was extracted via hydrophobic, reverse-phase, silica-based column. Our initial hypothesis was refuted, since LXA4 was increased in SHR (WKY: 0.33±0.05 vs. SHR: 0.79±0.08 ng/ml, p<0.05). As a result, we inhibited LXA4 synthesis in SHR with a 5-lipoxygenase (5-LOX) inhibitor Zileuton (10mg/kg/day i.p.) for 10 days. 5-LOX blockade did not change blood pressure (BP), but did cause a deterioration of vascular function in intrarenal and mesenteric resistance arteries in SHR. On the other hand, the blockade of FPR in SHR for 10 days with Cyclosporin H (CsH) and WRW4 (0.1 mg/kg/day) reduced BP (telemetry: SHR+control: 151±7.2 vs. SHR+CsH+WRW4: 138±0.4 mmHg, p<0.05) and left ventricle mass. FPR blockade also ameliorated acetylcholine-induced relaxation of intrarenal (Emax: SHR+control: 10±5 vs. SHR+CsH+WRW4: 28±6 %, p<0.05) and mesenteric resistance arteries (Emax: SHR+vehicle: 74±10 vs. SHR+CsH+WRW4: 99±0.6 %, p<0.05). From these data, we suggest that LXA4 does not act on FPR to promote resolution of inflammation. We believe that another factor binds FPR (e.g., F-MITs) and leads to vascular damage in SHR. In support of this, we observed that LXA4 phosphorylates estrogen receptor (ER) alpha Ser118 in aortic vascular smooth muscle cells (VSMC) and ER antagonist ICI-182 (100nM), but not FPR antagonist, abolishes these responses. On the other hand, FMITs increased phosphoERK 1/2 in VSMC and FPR antagonists blocked this increase. In conclusion, FMITs and LXA4 have opposite effects in SHR. LXA4 induces resolution of inflammation, possibly via ER activation, and F-MITs lead to damage via FPR activation.