The protective effect of superoxide dismutase mimetic M40401 on balloon injury-related neointima formation: role of the lectin-like oxidized low-density lipoprotein receptor-1.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the principal receptor for oxidized low-density lipoprotein (ox-LDL) in vascular endothelial cells (ECs), has recently been suggested to exert a pivotal role in atherogenesis, possibly by mediating ox-LDL-evoked endothelial dysfunction. On the other hand, LOX-1 expression seems to strongly correlate with the oxidative stress occurring in the vascular wall of experimentally injured blood vessels. Here, we investigated LOX-1 expression and superoxide generation during neointima formation in a balloon injury rat carotid artery model. To test this, we used M40401 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand], a synthetic superoxide dismutase mimetic that is a selective scavenger of superoxide. The injury was performed inserting the balloon catheter through the rat common carotid artery and after 14 days a histopathological analysis revealed a significant restenosis with smooth muscle cell proliferation and neointima formation that was associated with an enhanced expression of LOX-1, nitrotyrosine (the footprint of peroxynitrite) staining, and lipid peroxidation as assessed by malondialdehyde (MDA) formation. Pretreatment of rats with M40401 (0.5-10 mg/kg i.p. daily) reduced neointima formation, MDA accumulation, nitrotyrosine staining, and LOX-1 expression. Here, we show that removal of superoxide formation occurring in injured arteries reduces both neointima formation and LOX-1 expression and that this may represent a novel therapeutical approach in the treatment of vascular disorders in which proliferation of vascular smooth muscle cells and ox-LDL-related endothelial cell dysfunction occur.
Muscoli
Carolina
C
Faculty of Pharmacy, University of Catanzaro Magna Graecia, Complesso Nini' Barbieri, Roccelletta di Borgia, 88100, Catanzaro, Italy.
Sacco
Iolanda
I
Alecce
Wanessa
W
Palma
Ernesto
E
Nisticò
Robert
R
Costa
Nicola
N
Clementi
Fabrizio
F
Rotiroti
Domenicantonio
D
Romeo
Francesco
F
Salvemini
Daniela
D
Mehta
Jawahar L
JL
Mollace
Vincenzo
V
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000150:complications / Q000209:etiology; D002404:Catheterization / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism / Q000502:physiology*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013482:Superoxide Dismutase / Q000737:chemistry
C426066:M40401; C495136:OLR1 protein, rat; D009942:Organometallic Compounds; D020011:Protective Agents; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013482:Superoxide Dismutase