Polylactide Nanocapsules Attenuate Adverse Cardiac Cellular Effects of Lyso-7, a Pan-PPAR Agonist/Anti-Inflammatory New Thiazolidinedione

Giani Garcia (1, 2) , Jérôme Roy (1) , Ivan Pitta (3) , Dulcinéia Abdalla (4) , Andrea Grabe-Guimarães (2) , Vanessa Mosqueira (2) , Sylvain Richard (1)

1 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
2 UFOP - Universidade Federal de Ouro Preto
3 Federal University of Pernambuco [Recife]
4 USP - Universidade de São Paulo = University of São Paulo

Lyso-7 is a novel synthetic thiazolidinedione, which is a receptor (pan) agonist of PPAR α,β/δ,γ with anti-inflammatory activity. We investigated the cardiotoxicity of free Lyso-7 in vitro (4.5–450 nM), and Lyso-7 loaded in polylactic acid nanocapsules (NC) in vivo (Lyso-7-NC, 1.6 mg/kg). In previous work, we characterized Lyso-7-NC. We administered intravenously Lyso-7, Lyso-7-NC, control, and blank-NC once a day for seven days in mice. We assessed cell contraction and intracellular Ca2+ transients on single mice cardiomyocytes enzymatically isolated. Lyso-7 reduced cell contraction and accelerated relaxation while lowering diastolic Ca2+ and reducing Ca2+ transient amplitude. Lyso-7 also promoted abnormal ectopic diastolic Ca2+ events, which isoproterenol dramatically enhanced. Incorporation of Lyso-7 in NC attenuated drug effects on cell contraction and prevented its impact on relaxation, diastolic Ca2+, Ca2+ transient amplitude, Ca2+ transient decay kinetics, and promotion of diastolic Ca2+ events. Acute effects of Lyso-7 on cardiomyocytes in vitro at high concentrations (450 nM) were globally similar to those observed after repeated administration in vivo. In conclusion, we show evidence for off-target effects of Lyso-7, seen during acute exposure of cardiomyocytes to high concentrations and after repeated treatment in mice. Nano-encapsulation of Lyso-7 in polymeric NC attenuated the unwanted effects, particularly ectopic Ca2+ events known to support life-threatening arrhythmias favored by stress or exercise.

Mots clés: peroxisome proliferator-activated receptor-γ; cardiotoxicity; metabolic syndrome; atherosclerosis; contraction; calcium transient; ectopic diastolic Ca2+ events; polymeric nanoparticle

Domaines: Sciences du Vivant [q-bio]

Giani Garcia, Jérôme Roy, Ivan Pitta, Dulcinéia Abdalla, Andrea Grabe-Guimarães, et al.. Polylactide Nanocapsules Attenuate Adverse Cardiac Cellular Effects of Lyso-7, a Pan-PPAR Agonist/Anti-Inflammatory New Thiazolidinedione. Pharmaceutics, 2021, 13 (9), pp.1521. ⟨10.3390/pharmaceutics13091521⟩. ⟨hal-03354628⟩