Combined treatment with ultrasound-targeted microbubble destruction technique and NM-aFGF-loaded PEG-nanoliposomes protects against diabetic cardiomyopathy-induced oxidative stress by activating the AKT/GSK-3β1/Nrf-2 pathway

Abstract

The present study sought to investigate the effect of non-mitogenic acidic fibroblast growth factor (NM-aFGF) loaded PEGylated nanoliposomes (NM-aFGF-PEG-lips) combined with the ultrasound-targeted microbubble destruction (UTMD) technique on modulating diabetic cardiomyopathy (DCM)and the mechanism involved. Animal studies showed that the diabetes mellitus (DM) group exhibited typical myocardial structural and functional changes of DCM. The indexes from the transthoracic echocardiography showed that the left ventricular function in the NM-aFGF-PEG-lips + UTMD group was significantly improved compared with the DM group. Histopathological observation further confirmed that the cardiomyocyte structural abnormalities and mitochondria ultrastructural changes were also significantly improved in the NM-aFGF-PEG-lips + UTMD group compared with DM group. The cardiac volume fraction (CVF) and apoptosis index in the NM-aFGF-PEG-lips + UTMD group decreased to 10.31 ± 0.76% and 2.16 ± 0.34, respectively, compared with those in the DM group (CVF = 21.4 ± 2.32, apoptosis index = 11.51 ± 1.24%). Moreover, we also found significantly increased superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity as well as clearly decreased lipid hydroperoxide levels and malondialdehyde (MDA) activity in the NM-aFGF-PEG-lips + UTMD group compared with those in the DM group ( p < .05). Western blot analysis further revealed the highest level of NM-aFGF, p-AKT, p-GSK-3β1, Nrf-2, SOD2 and NQO1 in the NM-aFGF-PEG-lips + UTMD group. This study confirmed using PEGylated nanoliposomes combined with the UTMD technique can effectively deliver NM-aFGF to the cardiac tissue of diabetic rats. The NM-aFGF can then inhibit myocardial oxidative stress damage due to DM by activating the AKT/GSK/Nrf-2 signaling pathway, which ultimately improved the myocardial structural and functional lesions in diabetic rats.