Liraglutide reduces myocardial metalloproteinase 2 activity without attenuating doxorubicin-induced cardiac dysfunction in rats
M L S Fonseca, E H Brito, M G Monte, G Brandao, C S Granjeia, L P Carreira, L N P Cunha, M F Santos, K Okoshi, M P Okoshi, L A M Zornoff, S A R Paiva, B F Polegato, C Rodrigues TononAbstract
Background
Cancer is one of the leading worldwide causes of morbidity and mortality. Doxorubicin (DOX) is an effective chemotherapeutic agent; however it induces cardiotoxicity for which there is no effective treatment, potentially impairing quality of life and prognosis in cancer patients. Matrix metalloproteinases (MMPs) are responsible for degrading and remodeling extracellular matrix components and are increased following doxorubicin treatment in experimental models. MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs). Glucagon-like peptide-1 (GLP-1) analogs, such as liraglutide, have demonstrated cardiovascular benefits, and evidence suggests that liraglutide may influence collagen deposition and cardiac tissue fibrosis. However, no studies have evaluated the effects of liraglutide on myocardial collagen dynamics or MMP regulation.
Purpose
To evaluate the role of liraglutide on cardiac function and MMP-2 regulation in a rat model of DOX-induced cardiotoxicity.
Methods
Sixty male Wistar rats were allocated into four groups: Control (C), DOX (D), Liraglutide (L), and DOX + Liraglutide (DL). Animals in the L and DL groups received daily subcutaneous injections of liraglutide (0.6 mg/kg) for two weeks, while C and D received saline. On day twelve, D and DL rats received a single intraperitoneal DOX injection (20 mg/kg), while C and L received saline. Forty-eight hours after DOX administration, rats underwent echocardiographic and isolated heart functional assessment, followed by euthanasia and heart tissue collection for in-gel zymography and Western blot analyses. Statistical analysis: Two-way ANOVA (p < 0.05).
Results
DOX-treated rats exhibited impaired cardiac function compared with non-DOX-treated rats, as assessed by both echocardiography and isolated heart studies. Liraglutide treatment did not improve functional parameters (Figure 1). MMP-2 activity was higher in DOX-treated rats than non-DOX-treated rats and lower in liraglutide-treated rats than non-liraglutide-treated rats (Figure 2A). Troponin-T, Type I collagen, Type III collagen, and TIMP-2 expression were reduced in DOX-treated rats. Liraglutide reduced TIMP-2 and increased troponin-T and collagen I in myocardium. TIMP-4 expression did not differ between groups (Figure 2B).
Conclusion
DOX induces cardiac injury, as seen by impaired systolic and diastolic left ventricular function and reduced myocardial troponin-T expression. Concurrently, DOX increases cardiac MMP-2 activity and reduces TIMP-2 expression, leading to reduced myocardial collagen. Liraglutide increases myocardial troponin-T and reduces MMP-2 activity, without attenuating left ventricular cardiac dysfunction.