Cardioprotective effect of extracellular vesicles derived from ticagrelor-pretreated cardiomyocyte on hyperglycemic cardiomyocytes through alleviation of oxidative and endoplasmic reticulum stress

Abstract

Extracellular vesicles (EVs) 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 increased risks for major cardiovascular complications. Under DM, chronic hyperglycemia, and subsequent increase in the production of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. The purinergic drug ticagrelor is a P2Y12 receptor antagonist. Although it is widely used in cardioprotection, the underlying molecular mechanism of its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to understand how ticagrelor exerts its cardio-regulatory effects. For this purpose, we investigated the anti-oxidative and cardioprotective effect of EVs derived from ticagrelor-pretreated cardiomyocytes under DM conditions. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with EVs, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that ticagrelor-pretreated H9c2-derived EVs significantly decreased the hyperglycemia-induced aberrant ROS production, prevented the development of apoptosis and ER stress, and alleviated oxidative stress associated miRNA-expression profile. Importantly, EVs derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the EV profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through extracellular vesicular modulation behind its receptor-inhibition-related effects.

Extracellular Vesicles Isolated from Equine Adipose-Derived Stromal Stem Cells (ASCs) Mitigate Tunicamycin-Induced ER Stress in Equine Corneal Stromal Stem Cells (CSSCs)

“…Zhang and colleagues [104] found that human MSCs-derived EVs protect cardiac cells against hyperactive ER stress induced by hypoxia/reoxygenation (H/R) injury, through the downregulation of ER stress markers including GRP78, CHOP, IRE1α, and ATF6. Likewise, Bitirim and collaborators [105] demonstrated the efficacy of EVs in attenuating ER stress in hyperglycemic cardiomyocytes, thus confirming the great potential of EVs in countering the cellular distress associated with improper folding proteins.…”

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 anti-hypoxic 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.…”

Interactions between endoplasmic reticulum stress and extracellular vesicles in multiple diseases

“…Ticagrelor, which is widely used for cardioprotection, has anti-platelet as well as angiogenic effects. One study reported that cardiomyocyte-derived EVs pretreated with ticagrelor significantly reduced hyperglycemia-induced abnormal ROS production, prevented the development of apoptosis and ER stress, attenuated oxidative stress-related miRNA expression profiles, and enhanced endothelial cell migration and tube formation, thus exerting antioxidant and cardioprotective effects on hyperglycemic cardiomyocytes ( 61 ). These experiments demonstrated that EVs do not always induce ER stress and promote disease but may also inhibit ER stress and suppress disease.…”