722 NATURAL ACTIVATORS OF AUTOPHAGY PROTECT THE HEART FROM DOX-INDUCED CARDIOMYOPATHY

Abstract Introduction Heart failure is a frequent death cause for oncological patients who received treatment with doxorubicin (DOX). DOX administration inhibits autophagy in cardiomyocytes and causes myocardial damage. Natural activators of (NAA) such as trehalose, natural disaccharide, spermidine, putrescine-derived polyamine initially isolated from semen, were previously found to be promising candidates recover the autophagic flux treat cardiovascular diseases mice. Hypothesis The protects heart DOX-induced injury. Methods C57BL/6J WT mice fed ad libitum trehalose or spermidine drinking water 3 weekly injections DOX, reaching final cumulative dose 15 mg/kg. Echocardiographic, histological biochemical analyses performed 6 weeks after first DOX. Also, vitro experimentation was on neonatal rat primary cardiomyocytes. Results Mice treated had reduced systolic function (FS: 44±1.05% vs. 34.1±2.33%, n=6-8), but preserved left ventricular fractional shortening 34.1 [Office1]±2.33% 45.1±0.75%, n=6-8). Autophagy-deficient Beclin1+/- FS not protected by (35.4±2.48% n=7-8). developed fibrosis (0.1±0.08% 8.6±3.5%, n=5), this effect trehalose-fed that (8.6±3.5% 2±0.68%, n=4-5). increased levels damaged-mitochondria disposal (2.6±0.74 9.4±1.7 mitophagic bodies per TEM field, n=13) further boosted (9.4±1.7 24.1±1.45, n=13). mRFP-eGFP-Lc3-dots assay used evaluating reduction observed cells (51.9±4.57 29.9±3.52 red dots cell, n=34-51), while recovered (29.9±3.52 121.5±8.02 n=33-34). Mitochondrial biogenesis reporter ‘MitoTimer’ showed (0.8±0.38 3.3±0.9, n=5-6), receiving did (3.3±0.9 0.3±0.12, n=5-6). Similarly, 29.4±2.03 39±3.22, n=5-6) autophagy. Conclusion NAA-mediated mitophagy induction developing cardiomyopathy disposing damaged mitochondria. [Office1]Le virgole diventano punti