THE H2S-RELEASING NAPROXEN DERIVATIVE, ATB-346, PREVENTS NEOINTIMA FORMATION FOLLOWING CAROTID ARTERY LIGATION IN MICE

THE H2S-RELEASING NAPROXEN DERIVATIVE, ATB-346, PREVENTS NEOINTIMA FORMATION FOLLOWING CAROTID ARTERY LIGATION IN MICE

• Autor
• Anízia Karoline de Oliveira
• Co-autores
• Luciano dos Santos Aggum Capettini , Edenil Costa Aguilar , Stêfany Bruno de Assis Cau
• Resumo

•  

  INTRODUCTION: Intimal hyperplasia is critical event involved in the pathophysiology of arterial occlusive diseases. Cyclooxygenases (COXs) enhancement and hydrogen sulfide (H₂S) reduction are both mediators of vascular remodeling after vascular injury. Therefore, our hypothesis is ATB-346, a COX inhibitor linked to a H₂S donor moiety, prevents intimal hyperplasia in mice submitted to occlusion of the carotid artery (CA). OBJECTIVE: To investigate the effect of ATB-346 in arterial remodeling induced by carotid stenosis. METHODS: The procedures were approved by the local research ethics committee (protocol n°13/2019). Male C57BL/6 mice were surgically submitted to total occlusion of the left common CA and split into four groups (N=5-7): sham (false operated), stenosis, stenosis+naproxen (10mg/kg) and stenosis+ATB-346 (16mg/kg). Drugs were locally delivered by their inclusion in a polymer hydrogel. After 21 days, local blood perfusion was determined by doppler single point. Animals were euthanized, and CA were excised to morphometry analyses. Frozen sections were used for COX-1/COX-2 immunofluorescence staining and fluorescent probe detection of reactive oxygen species (ROS) and nitric oxide (NO). Data were expressed as mean±SEM and submitted to one-way ANOVA, followed by Tukey's post-test. RESULTS: Local perfusion was reduced in stenosis (48%) and stenosis+naproxen (34%) groups compared to sham. ATB-346 fully restored CA perfusion. ATB-346, but not naproxen, inhibited neointima formation induced by stenosis (sham: 1,794±410?m²; stenosis: 52,007±9,066?m²; naproxen: 46,140±6,142?m²; ATB-346: 669±44?m²,P<0.001). Staining intensity of COX-1 was ?6 times greater in stenosis group. Both treatments reduced COX-1 detection in CA. Importantly, abundant COX-2 immunoreactivity induced by stenosis was only prevented by ATB-346 (fluoresce intensity of COX-2/area: sham: 760±112; stenosis: 5,305±382; ATB-346: 1,934±296; P<0.001). Carotid stenosis increased ROS generation and reduced NO levels. Both drugs shown antioxidant effect. However, only ATB-346 restored NO levels (P<0.05).CONCLUSION: Therefore, ATB-346–derived H₂S has additional beneficial effects on COX inhibition to prevent vascular remodeling following CA occlusion.

• Palavras-chave
• Neointimal hyperplasia; ATB-346, cyclooxygenases, hydrogen sulfide
• Modalidade
• Comunicação oral
• Área Temática
• Inflamação e doenças vasculares