Vildagliptin improves vascular smooth muscle relaxation and decreases cellular senescence in the aorta of doxorubicin-treated rats

Abstract

IntroductionDoxorubicin (DOX) is a chemotherapeutic agent used in cancer treatment. Its use is limited by later toxicity to the cardiovascular system (CVS). Cellular senescence has been proposed as one mechanism of DOX toxicity. It has also been suggested that senescence reduction can improve the condition in many pathologies. We hypothesised that vildagliptin treatment can reduce senescence and thus improve the relaxation of vascular smooth muscle (VSM) in the aorta of a rat DOX model. MethodsThe rats received DOX and were treated with vildagliptin for 6 weeks. Thereafter, the rats were sacrificed, and the aorta prepared for measurements of VSM relaxation and RNA isolation to detect the level of senescence markers. To further prove the antisenescence effect of the main vildagliptin effector glucagon-like peptide 1(GLP-1), VSM cells (VSMCs) were incubated with DOX and treated with GLP-1. Subsequently, senescence was detected by senescence-associated beta-galactosidase (SA-β-gal) and by the presence of senescence markers. ResultsDOX in rats caused diminished relaxation of VSM to sodium nitrate and caused an increase in the senescence mRNA markers p16Ink4a and p27Kip1 and the senescence-associated secretory phenotype (SASP) IL-6 and IL-8. Vildagliptin treatment led to improved relaxation and a reduction in senescence and SASP markers. Furthermore, in VSMCs DOX increased SA-β-gal activity, p16Ink4a, p27Kip1, IL-6 and IL-8, and GLP1 treatment led to a decrease of both senescence and SASP markers. ConclusionIn summary we conclude that vildagliptin can reduce senescence and improve relaxation of vascular smooth muscle in the aorta of DOX-treated rats, and GLP-1 can reduce senescence of DOX-treated VSMCs. These data suggest that incretin-based drugs are promising candidates for patients suffering from late doxorubicin cardiovascular toxicity.