In vivo administration of Cerium Oxide Nanoparticles restores cardiac dysfunction in a rat model of early diabetes

Background: An in-depth study of nanomaterials is believed to open new ways for the development of advanced devices, medications, and other highly specific, effective, and personalized applications, aiding in the early diagnosis and treatment of various diseases. In this context, cerium oxide nanoparticles (CeONPs) have become a focus of intense research due to their unique antioxidant and anti-inflammatory properties, high chemical stability, biocompatibility, and large reactive surface area. Consequently, in vivo administration of CeONPs may offer a new preventive strategy against cellular oxidative stress and myocardial inflammation, both of which play critical roles in the pathophysiology of diabetic cardiomyopathy. Using a rat model of early diabetes, we investigated the potential of CeONPs to reach the heart, ameliorate cardiac function altered even in the early stages of hyperglycaemia, and counteract diabetes-induced microenvironmental changes in myocardial tissue. Additionally, we studied the cardiac function both at organ and cellular level after the administration of CeONPs in control rats to ensure their safe application. Methods: Adult Wistar rats with streptozotocin-induced type-1 diabetes (n = 29) were studied in comparison with a control group (n = 15). Diabetic rats were either untreated (n = 16) or treated with intraperitoneal injections of CeONPs three times a week (n = 13) for four weeks. At the end of the protocol, hemodynamics, cardiomyocyte contractility, and calcium transients were measured to assess cardiac performance. The potential cardioprotective mechanisms of CeONPs were also investigated through in vitro assays for ROS and RNS scavenging activity and transcriptomic analysis using real-time PCR. Moreover, cardiac electrical function and arrhythmia vulnerability were evaluated using telemetric electrocardiographic analysis and transmission electron microscopy (TEM) was employed to confirm the presence, morphology, and subcellular localization of CeONPs in cardiac and hepatic tissues. To evaluate the effects of CeONPs on healthy animals, an additional study was conducted on 12 control (CTRL) rats treated with CeONPs in comparison with CTRL. After four weeks, hemodynamic parameters, cardiomyocyte contractile properties, and calcium transients were measured. CeONPs were characterized, and their capacity to interact with proteins present in cardiac tissue were studied using LC-MS proteomic analysis. Results: In vivo treatment with CeONPs in a rat model of early diabetes resulted in an improvement in contractile performance and calcium dynamics at the cellular level as well as a partial recovery in cardiac mechanical properties. The observed cardioprotective effects in diabetic rats appear to be driven by reductions in oxidative and nitrosative stress, along with modulation of the circNCX1/Sirt1/Nrf2 pathway which activates the antioxidant response. CeONPs were found in both cardiac and hepatic tissues and, most importantly, these internalized CeONP clusters did not induce any morphological changes or electrical alterations, including arrhythmias or exacerbation of the typical diabetic bradycardia. Protein binding studies indicated that CeONPs form a protein corona preferentially with proteins involved in cardiomyocyte contractility and mitochondrial function. Finally, the administration of CeONPs in healthy control rats confirmed the safety of the nanoparticles and treatment protocol, with evidence of enhanced cardiac contractile performance at both cellular and organ levels. Conclusions: Our findings suggest that CeONPs may represent a novel, safe therapeutic strategy capable of preventing initial myocardial damage in the diabetic heart and slowing its progression toward an overt pathological condition.