Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice

Abstract

Background: Diabetes mellitus exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury. Methods: Adult male mice were fed a normal or a high-fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid-challenged nondiabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection. Results: Intramyocardial injection of diabetic serum sEV in the nondiabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or high glucose/high lipid-challenged nondiabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in nondiabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. A mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and high glucose/high lipid-challenged nondiabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and nondiabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in nondiabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced proapoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from patients with type 2 diabetes mellitus. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor. Conclusions: We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple antiapoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.

Native and Bioengineered Exosomes for Ischemic Stroke Therapy

“…Diabetic serum exosome injection to the non-diabetic heart caused poorer cardiac function recovery, larger infract size, and increased apoptosis of cardiomyocytes. It was confirmed through various analysis that miRNA-130b-3p was responsible for the cardiotoxicity, and its direct downstream targets were AMPKα1/α2, Birc6, and Ucp3 ( Gan et al, 2020 ). Microglia-derived exosomes were found to mediate neuroinflammation ( Kumar et al, 2017 ) and Alzheimer’s disease propagation ( Saeedi et al, 2019 ).…”

Extracellular vesicle microRNA cargoes from intermittent hypoxia-exposed cardiomyocytes and their effect on endothelium

“…The decreased EV microRNA-21-5p derived from heart failure patients impaired cardiac regenerative potential by inhibiting angiogenesis and cardiomyocyte survival [10]. And the enriched miR-130b-3p in dysfunctional adipocyte-derived EV was found by our team mediating diabetes-related cardiac injury through suppression of cardioprotective molecules expression in cardiomyocytes [11]. Therefore, systematical and precise dissection of the myocardium-derived EV moleculars under IH conditions is so important as that will help to determine the main mechanism of OSAS or IH-associated cardiovascular diseases, and subsequently aid to develop more effective and precise diagnosis and treatment in clinical practice.…”

Adipocyte‐derived extracellular vesicles in health and diseases: Nano‐packages with vast biological properties

“…This transfer involves the Ad‐EV cargo miR‐130b‐3p. By acting on downstream targets such as AMPKα1/α2, Birc6, and Ucp3, the transfer of this miRNA leads to deleterious effect on cardiac function, suggesting that small Ad‐EVs act as pro‐deleterious messengers 75 . By contrast, different studies have suggested the beneficial effects of ADSC‐EVs in cardiac recovery, rendering them a great potential for use as therapeutic tools in regenerative therapies 76 .…”