Open AccessTargeted delivery of protein arginine deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity
Author(s) -
Roberto Molinaro,
Mikyung Yu,
Grasiele Sausen,
Colette Bichsel,
Claudia Corbo,
Eduardo J. Folco,
Gha Young Lee,
Yuan Liu,
Yevgenia Tesmenitsky,
Eugenia Shvartz,
Galina K. Sukhova,
Frederik Kloss,
Kevin Croce,
Jinjun Shi,
Peter Libby
Publication year - 2021
Publication title -
cardiovascular research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.774
H-Index - 219
eISSN - 1755-3245
pISSN - 0008-6363
DOI - 10.1093/cvr/cvab074
Subject(s) - endothelium , fibrous cap , in vivo , endothelial stem cell , extracellular matrix , vulnerable plaque , ex vivo , medicine , inflammation , microbiology and biotechnology , pharmacology , immunology , pathology , in vitro , biology , biochemistry
Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage.