Anti-atherosclerotic effects of serelaxin in apolipoprotein E-deficient mice

Abstract

Background and aims: Serelaxin (SLX) is a recombinant form of human relaxin-2, a naturally occurring peptide that regulates maternal cardiovascular adaptations to pregnancy. It is unclear whether SLX has a therapeutic effect on atherosclerosis. Therefore, we investigated direct vascular effects of SLX in a mouse model of atherosclerosis.

Methods: 6-8 week-old female apolipoprotein E-deficient mice were fed a high-fat, cholesterol-rich diet for 6 weeks and additionally received a continuous treatment with vehicle or SLX (0.05 or 0.1 μg/h), during the last 4 weeks, via subcutaneously implanted osmotic mini-pumps. Vascular oxidative stress, vasorelaxation and atherosclerotic plaque development were assessed.

Results: Vascular oxidative stress was reduced in SLX-treated mice (vehicle: 322.67 RLU/s, SLX 0.05 μg/h: 119.76 RLU/s (p < 0.001 vs. vehicle), SLX 0.1 μg/h: 109.33 RLU/s (p < 0.001 vs. vehicle; p = 0.967 vs. 0.05 μg/h SLX)). Further SLX improved endothelium-dependent vasodilatation without influencing endothelium-independent vasorelaxation. Atherosclerotic plaque development was significantly reduced by SLX (vehicle: 0.38 ± 0.02 mm(2), 0.05 μg/h SLX: 0.32 ± 0.02 mm(2) (p = 0.047 vs. vehicle), 0.1 μg/h SLX: 0.29 ± 0.02 mm(2) (p = 0.002 vs. vehicle; p = 0.490 vs. 0.05 μg/h SLX)). Neither vascular macrophage, T-cell or neutrophil infiltration, nor collagen/vascular smooth muscle cell content differed between the groups. We observed a significant down-regulation of the angiotensin II type 1a receptor and a decrease in IL-6 and an increase in IL-10 plasma concentrations.

Conclusions: Our data demonstrates novel pleiotropic effects of SLX on vascular oxidative stress, endothelial dysfunction and atherosclerotic plaque burden. Therefore, SLX could serve as a new drug for the treatment of atherosclerosis-related diseases.

Keywords: Atherosclerosis; Endothelial dysfunction; Serelaxin.