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

Abstract

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.

Current perspectives on clinical use of exosomes as novel biomarkers for cancer diagnosis

“…Existing studies have reported that ticagrelor enhanced the release of cell-derived exosomes from the antihypoxic cardiac group by increasing cell proliferation in vitro (177). In addition, extracellular vesicles derived from cardiomyocytes pretreated with ticagrelor have a protective effect on hyperglycemic cardiomyocytes by attenuating oxidative and endoplasmic reticulum stress (178). Recently, Kulshreshtha et al confirmed that simvastatin, a HMG CoA inhibitor, mediates exosome release by altering MVBs transport and that its mediated reduction in monocyte-derived exosome secretion is protective in vitro model of atherosclerosis (179).…”