THU0340 IMPACT OF LANIFIBRANOR, A PAN-PPAR AGONIST, ON THE PULMONARY VASCULAR TONE
Authors: Chandran Nagaraj, Neha Sharma, Bence Nagy, Jean-Louis Junien, Pierre Broqua, Irena Konstantinova, Andrea Olschewski, Grazyna Kwapiszewska, Horst Olschewski
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Pulmonary hypertension (PH) is common in patients with fibrosing interstitial lung diseases (ILDs) such as systemic sclerosis (scleroderma) and has a significant impact on survival. The pan-peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor is currently being tested in a phase II clinical trial in scleroderma patients. Although, the antifibrotic effects of lanifibranor have been previously shown in preclinical mouse models of scleroderma and related PH (1), its effects in modulating the pulmonary vascular tone are largely unknown. <h3>Objectives</h3> To evaluate the acute effect of lanifibranor (pan-PPAR agonist) and selective PPAR agonists on the pulmonary vascular tone. <h3>Methods</h3> Freshly isolated intra-pulmonary arteries from explanted human and rat lungs were used in wire myography experiments to assess the acute effect on pulmonary vascular tone of pan-PPAR agonist -lanifibranor and the selective PPAR agonists PPARα -fenofibrate, PPARβ/δ -GW50156 and PPARγ –troglitazone (0.01μM-30μM) versus vehicle (DMSO). The intra-pulmonary arteries were pre-constricted with 300nM of the thromboxane A2 receptor agonist U46619. The contribution of endothelium and nitric oxide was investigated using both native and endothelium-denuded vessels, with and without the nitric oxide synthase inhibitor L-NAME. <h3>Results</h3> Isometric tension measurements in rat pulmonary arteries showed that lanifibranor and the selective PPAR agonists PPARβ/δ -GW50156 and PPARγ –troglitazone, induced a significant relaxation compared to their vehicle controls, whereas the PPARα agonist fenofibrate did not show any vasoactive effect on the pre-constricted arteries. Lanifibranor showed a significant vasodilatory effect already at 1µM whereas GW50156 and troglitazone showed significant vasodilatory effects starting from 10µM as compared to their vehicle controls. At the maximum concentration used (30µM), lanifibranor caused a relaxation response of -85% whereas GW50156 and troglitazone caused just -45% and -50% vasorelaxation (n=6), respectively. The vasodilation induced by pan-PPAR and selective PPAR agonists remained unaffected by pre-treatment of L-NAME or denuded endothelium. Lanifibranor had vasodilatory effects that were strongly superior to any of the selective PPAR agonists in the isolated pulmonary artery from the explanted human lungs (n=3). <h3>Conclusion</h3> The current study revealed that the pan-PPAR agonist lanifibranor caused a rapid dose-dependent relaxation in both rat and human intra pulmonary arteries which were superior to any other PPAR agonists suggesting additive effects of the pan-PPAR agonism. The observed vasoactive effects of pan-PPAR are independent of nitric oxide and endothelium, delineating the specific effect of PPAR agonism on the pulmonary artery smooth muscle cells. These results suggest that lanifibranor could be a promising therapy for vasculopathies such as PH observed in scleroderma patients. <h3>Reference</h3> [1] Avouac J et al. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann Rheum Dis. 2017 Nov;76(11):1931-1940. <h3>Disclosure of Interests</h3> Chandran Nagaraj: None declared, Neha Sharma: None declared, Bence Nagy: None declared, Jean-Louis Junien Shareholder of: shareholder at inventiva, Employee of: employee of inventiva, Pierre Broqua Shareholder of: shareholder at inventiva, Employee of: employee at Inventiva, Irena KONSTANTINOVA Shareholder of: shareholder at inventiva, Employee of: employee at Inventiva, Andrea Olschewski: None declared, Grazyna Kwapiszewska Grant/research support from: research grant from Inventiva, Horst Olschewski Grant/research support from: financial grant from Bayer,Actelion,Boehringer,roche,inventiva, Consultant for: Bellerophon, MSD, TEVA, menarini,Chiesi,Novartis,GSK,BAYER,Roche,Boehringer