Role of FPR1 Formyl Peptide Receptors in the Cardioprotective Actions of Annexin-A1 Against Ischaemia–Reperfusion (I–R) Injury

Abstract

M. Imran ∗, A. Keogh, E. Kotylar, C. Hayward, P. Macdonald, R. Prichard Heart Transplant Unit, St. Vincent’s Hospital, NSW, Australia Introduction: A high transpulmonary gradient (i.e. >10mmHg) secondary to severe left heart failure is associatedwith increasedmortality after heart transplantation and left ventricular assist device implantation. Endothelin receptor antagonists are useful in certain forms of pulmonary hypertension (PAH), but avoided in PAH due to LHF. In this small studywe assessed the effect of bosentan on right heart haemodynamics in LHF with high TPG. Methods: Four patients with advanced LHF and high TPG-unresponsive to vasodilator challenge with nitroglycerine infusion or inhaled nitric oxide (precluding transplant or LVAD) received bosentan (62.5mg or 125mg BD) supplied on compassionate usage by Actelion Pharmaceuticals Australia. Serial right heart catheterisations were performed. Results: One of four patients had no fall in TPG after six weeks therapy and bosentan was discontinued. Three of four patients showed a good response to bosentan. Patient #1: was on LVAD support, developed a TPG of 16mmHg, falling to <10 on bosentan allowing successful heart transplant at 2 months. Patient #2: three months bosentan therapy resulted in improvement inTPG from20 to 12mmHg, PVR from 421 to 218 dyne s cm−5 and cardiac 2 of the actions of full-length ANX-A1 and activates both formyl peptide receptor (FPR)1 and FPR2. Although their anti-inflammatory effects are largely mediated by FPR2, receptors responsible for ANX-A1-based cardioprotection have not been resolved. In this study, rat isolated hearts were Langendorff-perfused with physiological buffer at constant flow (10mL/min), subjected to global, no-flow 30-min ischaemia followed by 30-min reperfusion. Hearts (n= 6–8 per group) were randomly allocated to treatment during reperfusion with Ac-ANX-A12–26 (0.3 M) in absence or presence of either non-selective FPR1/FPR2 antagonist Boc-2 (10 M), FPR2-selective antagonist Quinc-7 (10 M) or FPR1-selective antagonist Cyclosporin-H (1 M). Upon reperfusion, LV developed pressure (LVDP) was significantly reduced compared to pre-ischaemic baseline, and remained depressed during reperfusion. Lactate dehydrogenase (LDH) release was significantly elevated during reperfusion compared to sham (p= 0.001). In comparison, Ac-ANX-A12–26 treated hearts elicited complete recovery of LVDP by 10min reperfusion (p< 0.01), and LDH release was significantly attenuated (p= 0.005). Interestingly, preservation of LV function and cell viability mediated by Ac-ANXA12–26 were prevented by Boc-2, partially attenuated by Cyclosporin-H, but were unaffected by Quinc-7. Our findings suggest administration of Ac-ANX-A12–26 on reperfusion rescues LV function likely via activation of index from 1.7 to 2.0 l/min/m . He remains under consideration for heart transplant. Patient #3: bosentan for six months resulted inTPGfall from27 to18mmHg,PVRfrom 424 to 300 dyne s cm−5 with improvement in symptoms. Conclusion: Bosentan therapy can diminish disproportionately elevated TPG, secondary to left heart failure, facilitating definitive therapy (LVAD implant or transplant). http://dx.doi.org/10.1016/j.hlc.2012.05.232