Cardioprotection mediated by exosomes is impaired in the setting of type II diabetes but can be rescued by the use of non‐diabetic exosomes in vitro

Abstract

Many patients with ischaemic heart disease also have diabetes. As myocardial infarction is a major cause of mortality and morbidity in these patients, treatments that increase cell survival in response to ischaemia and reperfusion are needed. Exosomes—nano‐sized, lipid vesicles released from cells—can protect the hearts of non‐diabetic rats. We previously showed that exosomal HSP70 activates a cardioprotective signalling pathway in cardiomyocytes culminating in ERK1/2 and HSP27 phosphorylation. Here, we investigated whether the exosomal cardioprotective pathway remains intact in the setting of type II diabetes. Exosomes were isolated by differential centrifugation from non‐diabetic and type II diabetic patients, from non‐diabetic and Goto Kakizaki type II diabetic rats, and from normoglycaemic and hyperglycaemic endothelial cells. Exosome size and number were not significantly altered by diabetes. CD81 and HSP70 exosome markers were increased in diabetic rat exosomes. However, exosomes from diabetic rats no longer activated the ERK1/2 and HSP27 cardioprotective pathway and were no longer protective in a primary rat cardiomyocytes model of hypoxia and reoxygenation injury. Hyperglycaemic culture conditions were sufficient to impair protection by endothelial exosomes. Importantly, however, exosomes from non‐diabetic rats retained the ability to protect cardiomyocytes from diabetic rats. Exosomes from diabetic plasma have lost the ability to protect cardiomyocytes, but protection can be restored with exosomes from non‐diabetic plasma. These results support the concept that exosomes may be used to protect cardiomyocytes against ischaemia and reperfusion injury, even in the setting of type II diabetes.

Exosomes mediate sensory hair cell protection in the inner ear

“…In addition, our proteomics analysis identified numerous (HSPB1). This exosome-driven, HSP70/TLR4-induced signaling cascade protects cardiomyocytes against ischemia/reperfusion injury (58,66). A similar mechanism may underlie the protective effect of exosomes against hair cell death.…”

Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury

“…Additionally, induced exosomal HSP70, which was isolated from diabetic rats, failed to activate the ERK1/2 and HSP27 cardioprotective pathway in normal rat cardiomyocytes with hypoxia/reoxygenation, indicating that hyperglycemia might also abolish the cardioprotective effects of exosomal HSP70 (Davidson et al, ). As for the mechanisms involved, the impaired cardioprotective effects of diabetic exosomal HSP70 were possibly attributed to the masking, modification or damage of the epitope of HSP70 on the exosome (Davidson et al, ).…”

Engineered Exosomes With Ischemic Myocardium‐Targeting Peptide for Targeted Therapy in Myocardial Infarction

“…Regenerative medicine has been developed in recent years, such as mesenchymal stem cell (MSC) transplantation to repair myocardial infarction (MI) and restore heart function in both animal experiments1, 2, 3, 4 and patients 5, 6, 7, 8, 9, 10. There is mounting evidence that MSCs help repair or regenerate damaged tissues, primarily by means of secreting paracrine factors,11 including antiapoptotic factors,12 proangiogenic factors,13 and exosomes,14 rather than via the differentiation into cardiomyocytes 15, 16, 17…”