Ticagrelor-Pretreated Cardiomyocyte Derived Exosomes Provide Cardioprotection Under Hyperglycemia Through Alleviation In Oxidative Stress, Apoptosis, And ER-Stress

Exosomes play important roles in Diabetes Mellitus (DM) via connecting the immune cell response to tissue injury, besides stimulation to muscle insulin resistance, while DM is associated with increase risks for major cardiovascular complications. Under DM, chronic hyperglycemia and subsequent augmentation of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. Although a P2Y12 receptor inhibitor, ticagrelor, is widely used in cardioprotection, its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to investigate the anti-oxidative and cardioprotective effect of exosomes, derived from ticagrelor pretreated-cardiomyocytes. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with exosomes, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that exosomes derived from ticagrelor-pretreated H9c2-cells significantly decreased the aberrant ROS production, prevented the development of apoptosis and ER stress under hyperglycemia, and alleviated oxidative stress associated with a miRNA-expression profile. Importantly, exosomes derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the exosome profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through exosomal modulation behind its receptor-inhibitor related action.