Published online before print October 2, 2003, doi: 10.1161/01.RES.0000099062.55042.9A
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Submitted on October 30, 2002
Revised on September 17, 2003
Accepted on September 22, 2003
Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice
Ziad Mallat *;
From Institut National de la Santé et de la Recherche Médicale (Z.M., A.G., J.S.S., B.E., R.M., A.T.), INSERM U541, et Institut Fédératif de Recherche Paris VII, Hôpital Lariboisière, Paris, France; INSERM U 533, Faculte des Sciences (V.S., G.L.), Nantes, France; INSERM U343 and TxCell, Bat. ARC (V.B., H.G.), Hôpital de l'Archet, Nice, France.
* To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.
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-
B within plaques (P<0.05). In vitro, treatment with Y-27632 inhibited p65 phosphorylation and degradation of IB
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.
Key words: atherosclerosis • inflammation • lymphocytes • signal transduction • nuclear factor-
B
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