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Published on: September 26, 2018
Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice
Ziad Mallat1, Andrea Gojova, Vincent Sauzeau
1Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Paris, France. mallat@larib.inserm.fr
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.
Insights
Inhibiting Rho kinase significantly reduced early atherosclerosis development in mice by decreasing plaque size and T cell accumulation. This suggests Rho kinase inhibitors may be a potential treatment for atherosclerosis.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Rho GTPases are involved in inflammatory signaling pathways.
- Atherosclerosis is a chronic inflammatory disease of the arteries.
Purpose of the Study:
- To investigate the effect of Rho kinase inhibition on the development of atherosclerosis in vivo.
- To explore the potential of Rho kinase inhibitors as a therapeutic strategy for atherosclerosis.
Main Methods:
- Low-density lipoprotein receptor (LDLR) knockout mice were treated with a Rho kinase inhibitor (Y-27632) or saline.
- Atherosclerotic lesion size, T lymphocyte accumulation, and NF-kappaB signaling were assessed.
- In vitro studies examined the effect of Y-27632 on macrophage and T cell function.
Main Results:
- Y-27632 treatment significantly reduced atherosclerotic lesion size in the aortic sinus and thoracic aorta.
- Inhibition of Rho kinase decreased T lymphocyte accumulation and NF-kappaB activation within plaques.
- In vitro, Y-27632 inhibited macrophage inflammatory responses and T cell proliferation.
Conclusions:
- Inhibition of Rho kinase effectively limits early atherosclerotic plaque development in LDLR knockout mice.
- Rho kinase plays a critical role in the inflammatory processes underlying atherogenesis.
- Rho kinase inhibitors represent a promising therapeutic target for atherosclerosis treatment.
