Small Extracellular Vesicle External Surface Adiponectin-Mediated Adipocytes Cardiomyocytes Comm

Small extracellular vesicles (sEVs) from adipocytes modulate cardiomyocyte response to ischemic heart injury and post-MI remodeling. In non-diabetic mice, intramyocardial injection of adipocyte-derived sEVs attenuated adverse remodeling and improved cardiac function after myocardial infarction (MI) with 90 minutes of ischemia followed by four weeks of reperfusion.

The protective effect was attenuated or absent in diabetic hearts. In isolated adult non-diabetic cardiomyocytes, sEV exposure rapidly activated cell-salvage kinases (ERK, AMPK, ACC) and reduced oxidative-stress–induced death, suggesting surface molecules mediate protection.

Exo-Flow analysis identified adiponectin (APN) enriched on the sEV external surface; sEVs from APN knockout or APN-neutralized sEVs failed to confer protection. Protection required AdipoR1 signaling; sEVs were ineffective in AdipoR1-deficient mice and in mice with GRK2 overexpression, which inactivates AdipoR1.

Diabetes increased cardiac GRK2 and AdipoR1 phosphorylation, blunting sEV signaling. Restoring AdipoR1 function by a phosphorylation-resistant AdipoR1 (AdipoR1S205A) via AAV9 rescued sEV cardioprotection in diabetic mice.

The data support APN-enriched sEV external surfaces as mediators of adipocyte–cardiomyocyte communication, disrupted by diabetes through GRK2-mediated AdipoR1 inactivation. Uncertainty remains regarding long-term translational implications and potential variability across models.