Long term Rho-kinase inhibition ameliorates endothelial dysfunction in LDL-Receptor deficient mice
Kerstin Steioff1, Hartmut Rütten, Andreas E Busch
1Sanofi-Aventis Pharma GmbH, Therapeutic Department Cardiovascular Diseases, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
Abstract:
Chronic inhibition of Rho-kinase has been recently implicated in retardation of atherogenesis induced by high-fat diet in low-density lipoprotein receptor deficient (LDLR-/-) mice. However, it remains to be examined whether long-term Rho-kinase inhibition will reduce vascular dysfunction in this model. LDLR-/- mice on a high-fat diet were treated either with saline (LDLR-/-) or with the Rho-kinase inhibitor Fasudil (HA1077, 5-Isoquinolinesulfonyl homopiperazine, 100 mg/kg/day by gavage, LDLR-/- +Fasudil) for 10 weeks. Fasudil-treatment normalized endothelial function (measured by means of endothelium-dependent vasorelaxation) in LDLR-/- +Fasudil, to the level of controls (C57BL/6J). No tolerance toward Rho-kinase inhibition has been detected in Fasudil-treated animals. We conclude that long-term Rho-kinase inhibition normalizes endothelial function without development of tolerance.
Insights
Long-term Rho-kinase inhibition with Fasudil normalized endothelial function in mice with atherosclerosis. This study found no tolerance to the drug
Area of Science:
- Cardiovascular Research
- Pharmacology
Background:
- Atherosclerosis is accelerated by high-fat diets in low-density lipoprotein receptor deficient (LDLR-/-) mice.
- Chronic Rho-kinase inhibition has shown potential in retarding atherogenesis.
Purpose of the Study:
- To investigate the long-term effects of Rho-kinase inhibition on vascular dysfunction in LDLR-/- mice on a high-fat diet.
- To determine if tolerance develops with sustained Rho-kinase inhibition.
Main Methods:
- LDLR-/- mice were fed a high-fat diet for 10 weeks.
- Mice were treated daily with either saline or the Rho-kinase inhibitor Fasudil (100 mg/kg/day).
- Endothelial function was assessed via endothelium-dependent vasorelaxation.
Main Results:
- Fasudil treatment normalized endothelial function in LDLR-/- mice to control levels.
- No tolerance to Rho-kinase inhibition was observed in Fasudil-treated animals.
- Vascular dysfunction was significantly improved by long-term Fasudil administration.
Conclusions:
- Long-term Rho-kinase inhibition effectively normalizes endothelial function in a mouse model of diet-induced atherosclerosis.
- Sustained use of Fasudil does not lead to the development of tolerance.
- Rho-kinase inhibition represents a promising therapeutic strategy for vascular dysfunction associated with atherosclerosis.
