O74 EPOXYEICOSATRIENOIC ACIDS ANALOGUE (EET-A) FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED HEART FAILURE WITH NEPHROTIC SYNDROME

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Background and Objective: Doxorubicin (DOXO) is still commonly used anthracycline for the treatment of many types of cancers, but its application is burdened with a high risk of cardiotoxicity. The exact mechanisms of DOXO cardiotoxicity are still under investigation. Currently it is believed that the formation of topoisomerase II beta complex with DOXO, together with increased levels of reactive oxygen species (ROS) leads to cardiotoxicity. However, many additional mechanisms can weaken the heart and contribute to HFrEF development. Few years ago, new hypothesis emerged linking the DOXO-cardiotoxicity with the diminished expression of CYP2J2, an isoform of cytochrome P450, which is responsible for epoxyeicosatrienoic acids (EETs) formation. EETs were shown to exhibit vasodilation, decrease inflammation and to promote sodium excretion. Cardiac CYP2J2 overexpression decreased the cardiac injury in DOXO-treated mice. Hence, we decided to test the effectiveness of the EETs analogue (EET-A) in a model of DOXO-induced HFrEF with nephrotic syndrome. Methods: DOXO was administered to male Ren-2 transgenic rats (TGR) via five intravenous injections (cumulative dose 10 mg/kg of body weight). The long-term survival (20 weeks) of rats treated with EET-A (10 mg/kg of body weight administered in drinking water) was compared to ACE inhibitor (ACEi). Cardiac function was evaluated by echocardiography, urine and blood were collected for analysis. Results: The treatment with EET-A did not improve survival and cardiac function measured by echocardiography, however there was a clear renoprotective effect observed. Albuminuria was significantly lower in the EET-A treated group, when compared to ACEi. Plasma albumin did not change after 4-week treatment with EET-A, whereas in both placebo and ACEi a significant decrease was recorded. Conclusions: Despite the lack of improvement of survival, the beneficial effect of EET-A on the kidneys supports its potential for nephrotic syndrome treatment. Supported by MH CZ - DRO (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001”)