Lipoxygenase inhibitor ML351 dysregulated an innate inflammatory response leading to impaired cardiac repair in acute heart failure.

Abstract

The presistent increase of 12/15 lipoxygenase enzyme activity is correlated with uncontrolled inflammation, leading to organ dysfunction. ML351, a potent 12/15 lipoxygenase (12/15LOX) inhibitor, was reported to reduce infarct size and inflammation in a murine ischemic stroke model. In the presented work, we have applied three complementary experimental approaches, in-vitro, ex-vivo, and in-vivo, to determine whether pharmacological inhibition of 12/15LOX could dampen the inflammatory response in adult mice after Kdo2-Lipid A (KLA) as an endotoxin stimulator or post myocardial infarction (MI). Male C57BL/6 (8-12 weeks) mice were subjected to permanent coronary ligation thereby inducing acute heart failure (MI-d1 and MI-d5) for in-vivo studies. 12/15LOX antagonist ML351 (50 mg/kg) was subcutaneously injected 2 h post-MI, while MI-controls received saline. For ex-vivo experiments, ML351 (25 mg/kg) was injected as bolus after 5 min of inflammatory stimulus (KLA 1 μg/g) injection. Peritoneal macrophages (PMɸ) were harvested after 4 h post KLA. For in-vitro studies, PMɸ were treated with KLA (100 ng/mL), ML351 (10 µM), or KLA + ML351 for 4 h, and inflammatory response was evaluated. In-vivo, 5LOX expression was reduced after ML351 administration, inducing a compensatory increase of 12LOX that sensitized PMɸ toward a proinflammatory state. This was marked by higher inflammatory cytokines and dysregulation of the splenocardiac axis post-MI. ML351 treatment increased CD11b+ and Ly6Chigh populations in spleen and Ly6G+ population in heart, with a decrease in F4/80+ macrophage population at MI-d1. In-vitro results indicated that ML351 suppressed initiation of inflammation while ex-vivo results suggested ML351 overactivated inflammation consequently delaying the resolution process. Collectively, in-vitro, ex-vivo, and in-vivo results indicated that pharmacological blockade of lipoxygenases using ML351 impaired initiation of inflammation thereby dysregulated acute immune response in cardiac repair.

• Authors: Bochra Tourki, Laurence M Black, Vasundhara Kain, Ganesh V Halade
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 139 Pg. 111574 (Jul 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 33862495 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• 12-15-lipoxygenase
• Anti-Inflammatory Agents, Non-Steroidal
• Isoxazoles
• Lipoxygenase Inhibitors
• ML351 compound
• Naphthalenes
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Arachidonate 5-Lipoxygenase (metabolism)
• Echocardiography
• Heart Failure (drug therapy, physiopathology)
• Immunity, Innate
• Inflammation (pathology)
• Isoxazoles (pharmacology, therapeutic use)
• Lipoxygenase Inhibitors (pharmacology, therapeutic use)
• Macrophage Activation (drug effects)
• Macrophages, Peritoneal (drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (chemically induced, drug therapy, pathology)
• Naphthalenes (pharmacology, therapeutic use)