title: Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice.
abstract: Members of the Rho family of small GTPases have been recently implicated in inflammatory signaling. We examined the effect of in vivo inhibition of Rho kinase on atherogenesis in mice. Low-density lipoprotein receptor (LDLR) knockout (KO) mice fed a cholate-free high-fat diet received daily intraperitoneal injection of saline (n=8, control group) or Y-27632 (30 mg/kg, n=9), a specific Rho kinase inhibitor. After 9 weeks, Y-27632 treatment resulted in significant in vivo inhibition of Rho kinase activity (P=0.004). Body weights, arterial blood pressures, and plasma cholesterol levels were comparable in both groups. Atherosclerotic lesion size in the aortic sinus and thoracic aorta of mice treated with Y-27632 was reduced by respectively 35% and 29% in comparison with the saline-treated animals (P=0.006 and P=0.03, respectively). This was associated with a significant reduction in T lymphocyte accumulation (P=0.035) and expression of p65 subunit of NF-kappaB within plaques (P<0.05). In vitro, treatment with Y-27632 inhibited p65 phosphorylation and degradation of IkappaBalpha in mouse peritoneal macrophages and significantly inhibited concanavalin A-induced proliferation of spleen-derived T cells (P<0.001). In conclusion, inhibition of Rho kinase significantly limits early atherosclerotic plaque development in the LDLR KO mice. This study identifies Rho kinase inhibitors as potential candidates for the treatment of atherosclerosis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Paris, France. mallat@larib.inserm.fr
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Andrea
authors.initials: A
authors.lastname: Gojova
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.forename: Valérie
authors.initials: V
authors.lastname: Brun
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Bruno
authors.initials: B
authors.lastname: Esposito
authors.forename: Régine
authors.initials: R
authors.lastname: Merval
authors.forename: Hervé
authors.initials: H
authors.lastname: Groux
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001161:Arteriosclerosis / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004041:Dietary Fats; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005526:Food, Formulated; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D051996:Transcription Factor RelA; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011725:Pyridines; D011973:Receptors, LDL; D051996:Transcription Factor RelA; C108830:Y 27632; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases