Efeito das estatinas sobre a progressão da cardiomiopatia induzida por doxorrubicina

Abstract

The cardiotoxicity anthracycline-induced has been documented for decades, and the mechanisms that lead to this limiting side effect are uncertain. Some evidence points to increase in oxidative stress and activation of apoptotic pathways, but as the progression of this condition occurs, is unknown. In addition, many therapeutic strategies have been studied in order to minimize and/or avoid cardiotoxicity, and one of them is statins. Our study aimed to understand the progression of cardiomyopathy doxorubicin-induced (DOX) and to test rosuvastatin (ROS), a potent statin, as adjunctive therapy to minimize cardiotoxic effects. We used 96 sprague-dawley rats divided into two studies; one on the progression of cardiomyopathy where we used a dose of 1 mg / kg / day DOX for 10 days and the animals were divided into 4 control groups: DOX1, DOX2 and DOX4 (sacrificed at 1, 2 and 4 weeks after the termination of infusion of doxorubicin respectively). In the other study using rosuvastatin, the animals were divided into 4 groups: Control, DOX (idem DOX4), ROS (received 20 mg / kg / day during and after administration of DOX) and DOX-ROS. Experiments were performed to analyze cardiac function (Langendorff), vascular function (organ bath), and analysis of antioxidant enzymes, oxidative stress markers, optical and electronic microscopy. We first found ultrastructural alterations such as cardiomyocyte disorganization, nuclear alterations, cytoplasmic and mitochondrial vacuolization with progressive worsening, as well as a reduction in catecholaminergic response and later activation of apoptotic pathways and loss of function. When we included rosuvastatin in a therapeutic regimen, our results demonstrated a reduction of oxidative stress, deposition of collagen fibers in the cardiac interstice, preservation of cardiac microcirculation and response to endothelium-dependent vasodilators in the mesenteric arterial bed. With these results, we can conclude that doxorubicin-induced cardiomyopathy occurs continuously and progressively, where morphological alterations appear to occur primarily where functional modifications later become evident. The therapeutic regimen with ROS seems to be promising, since it has preserved vascular function and structure as well as reduced oxidative stress, possibly imparting cardioprotection in a chemotherapeutic regimen.