Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF

Area of Science:

• Cardiovascular Biology
• Neuroimmunology
• Molecular Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a growing public health issue.
• HFpEF pathophysiology involves complex neuroinflammation and sympathetic nervous system activation.
• The role of small extracellular vesicles (sEVs) in heart-brain crosstalk in HFpEF is not well understood.

Purpose of the Study:

• To investigate the role of cardiomyocyte-derived sEVs in HFpEF.
• To explore the mechanism of neuroinflammation and sympathetic activation in HFpEF.
• To identify potential therapeutic targets for HFpEF.

Main Methods:

• A mouse model of HFpEF was created using a high-fat diet and l-NAME.
• Microglial activation was assessed, and microglial depletion was performed using PLX3397.
• sEVs were isolated from HFpEF mice and treated with BV2 microglia; miR-200c-3p levels were analyzed.
• GW4869 was used to inhibit sEV biogenesis, and a miR-200c-3p sponge/mimic/inhibitor was employed.

Main Results:

• HFpEF mice showed microglial activation and hypothalamic inflammation.
• Depleting microglia improved cardiac function and reduced sympathetic activity.
• Cardiomyocyte-derived sEVs induced microglial M1 polarization, hypothalamic inflammation, and sympathetic activation.
• miR-200c-3p was upregulated in HFpEF sEVs and promoted inflammation, while its inhibition reversed these effects.
• DUSP1 was identified as a downstream target of miR-200c-3p.

Conclusions:

• HFpEF induces cardiomyocytes to release sEVs containing miR-200c-3p.
• These sEVs cause hypothalamic inflammation and sympathetic activation, exacerbating cardiac dysfunction.
• Targeting sEV-mediated communication offers a potential therapeutic strategy for HFpEF.