Abstract 114: Increased Circulating Levels of Mitochondrial N-Formyl Peptides Leads to Vascular Dysfunction and High Blood Pressure in Spontaneously Hypertensive Rats

Abstract

Aims: The most powerful signaling pathway that induces actin polymerization and movement in neutrophils is due to formyl peptide receptor (FPR) activation. FPR was originally identified by its ability to bind bacterial N-formyl peptides. Mitochondria carry hallmarks of their bacterial ancestry and one of these hallmarks is that this organelle uses an N-formyl-methionyl-tRNA as an initiator of protein synthesis. Consequently, mitochondrial N-formyl peptides (F-MITs) are recognized by FPR. Recently, we have observed that FPR is expressed in endothelial and vascular smooth muscle cells (VSMC). We hypothesized that increased plasma levels of F-MITs activates FPR and contributes to microvascular damage and hypertension. Methods: Male SHR (12-week old) were treated for 10 days with FPR antagonist cocktail: Cyclosporin H (CsH, 0.1 mg/kg/day i.p. ) and WRW4 (0.1 mg/kg/day i.p. ) or vehicle. Blood pressure (BP) was measured by telemetry. We also treated Wistar rats (12 week old) with F-MITs (formylated peptide corresponding to the NH2-terminus of mitochondria ND6; 0.02 mg/rat/day i.p. ) or non-formylated peptides (control) for 10 days. Blood was collected to measure F-MITs. Intrarenal arteries and mesenteric resistance arteries (MRA) were isolated and mounted in a wire myograph. Wistar VSMCs were treated with F-MITs (20 min, 10 μM) or control in the presence or absence of FPR antagonists to evaluate actin polymerization. T-test *p<0.05; n=5-6. Results and Conclusion: F-MITs plasma levels were increased in SHR (1.7-fold* vs. Wistar). FPR blockade decreased BP (SHR + vehicle: 151 ± 7.2 vs. SHR+CsH+WRW4: 138 ± 0.4* mmHg) and ameliorated acetylcholine-induced relaxation (Intrarenal; Emax: SHR+vehicle: 10 ± 5 vs. SHR+CsH+WRW4: 28 ± 6* %); (MRA; Emax: SHR+vehicle: 74±10 vs. SHR+CsH+WRW4: 99±0.6* %). F-MITs infusion increased BP in Wistar rats (Control: 133 ± 1.9 vs. F-MITs: 145 ± 4.7* mmHg) and decreased acetylcholine-induced relaxation (EC50; MRA: Control: -8.765 ± 0.05 vs. F-MIT: -8.348 ± 0.08*) (Emax; Intrarenal: Control: 63±4 vs. F-MIT: 46 ± 3* %). F-MITs induced VSMCs actin polymerization (1.8 fold* vs. control) and FPR blockers abolished this result. In conclusion, FMITs play a role in vascular dysfunction and hypertension via FPR activation.