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Effects of MMP-2 inhibition in doxorubicin-induced cardiotoxicity in rats

Grant number: 18/03381-9
Support type:Regular Research Grants
Duration: August 01, 2018 - October 31, 2020
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Bertha Furlan Polegato
Grantee:Bertha Furlan Polegato
Home Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Doxorubicin is a chemotherapeutic drug use in the treatment of malignant neoplasms. It is highly effective; however, it can cause cardiotoxicity, the most serious side effect of doxorubicin treatment. Chronic cardiotoxicity manifests as left ventricular dilation and cardiac dysfunction, which increases the mortality of these patients and worsens the quality of life. The pathophysiology of cardiotoxicity is not yet clearly understood, but doxorubicin infusion could culminate in mitochondrial dysfunction, increased oxidative stress, and activation of matrix metalloproteinases (MMPs). MMPs are proteolytic enzymes, which degrade components of the extracellular matrix and participate in the process of ventricular remodeling actively. MMP activity is regulated by specific tissue inhibitors (TIMPs). The aim of the study is to evaluate the effect of MMP inhibition on morphology and left ventricular function in the experimental model of doxorubicin-induced cardiotoxicity in rats. Eighty male Wistar rats will be used, which will be allocated in 4 groups: control, doxorubicin, inhibition of MMP and doxorubicin + inhibition of MMP. Inhibition of MMP will be performed by injection of doxycycline (5mg / kg, PI) once a week for 4 weeks. Doxorubicin (5mg / kg, PI) will be injected once a week for 4 weeks, always 48 hours after the injection of doxycycline. After 4 weeks, echocardiogram and isolated heart study will be performed to evaluate left ventricular function follow by euthanasia of the animals to collect the biological material. Evaluation of the oxidative stress and enzymatic complexes of the mitochondrial respiratory chain .activity will be analyze by spectrophotometry, MMP activity will be measure by zymography and protein expression of MMP and TIMP will be evaluate by Western blot. Statistical analysis: Two-way ANOVA, with statistical significance of 5%. (AU)

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