Rationale Glucocorticoid administration increases cardiovascular risk but inhibits neointimal proliferation in animal models. Glucocorticoid activity in target tissues is regulated by the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD); type-1 regenerates active glucocorticoids and type-2 inactivates glucocorticoids. Both 11β-HSD isozymes are expressed in vessel wall as well as in liver and adipose tissue; they may modulate vascular remodelling by acting locally or by influencing systemic risk factors. This study investigated effects of these isozymes on post-angioplasty neointimal proliferation.
Methodology Wire angioplasty was conducted in femoral arteries of C57Bl/6J, Apo-E knockout, 11β-HSD1 knockout, Apo-E/11β-HSD1 double-knockout and 11β-HSD2 knockout mice. Effects of pharmacological inhibition of 11β-HSD1 (Compound 544, 30 mg/kg/day) were also studied. Vascular lesions were assessed using novel optical projection tomography and standard histology.
Results 11β-HSD1 deletion or inhibition resulted in ∼35% reduction in neointimal volume with corresponding increase in lumen size in western-diet fed Apo-E knockout mice but had no significant effect in chow-fed C57Bl/6J mice. Reduced neointimal proliferation was associated with reduction in weight gain, insulin resistance, systolic blood pressure and macrophage content of neointimal lesions. 11β-HSD2 knockout mice had substantially higher blood pressure than C57Bl/6J mice. Neointimal proliferation, however, was similar in both groups, albeit 11β-HSD2 knockout mice having higher neointimal macrophage content.
Conclusion 11β-HSD1 inhibition ameliorates multiple cardiovascular risk factors and reduces neointimal proliferation only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose. Any local amplification (with disruption of 11β-HSD2) or reduction (with disruption of 11β-HSD1) in glucocorticoid concentration within the vessel wall is likely to be insufficient to overcome the effect of systemic risk factors on neointimal proliferation.
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