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 activation.
• The role of small extracellular vesicles (sEVs) in heart-brain crosstalk in HFpEF is understudied.

Purpose of the Study:

• To investigate the role of cardiomyocyte-derived sEVs in HFpEF pathogenesis.
• To explore the impact of sEVs on microglial activation and hypothalamic inflammation.
• To identify molecular mechanisms linking cardiac dysfunction to neuroinflammation in HFpEF.

Main Methods:

• Developed a mouse model of HFpEF using a high-fat diet and l-NAME.
• Administered microglial depletion agent (PLX3397) and sEV biogenesis inhibitor (GW4869).
• Analyzed sEVs for microRNA content (miR-200c-3p) and their effect on microglia (BV2 cells) and in vivo models.

Main Results:

• HFpEF mice showed microglial activation, hypothalamic inflammation, and sympathetic hyperactivity.
• Myocardial sEVs from HFpEF mice induced microglial M1 polarization and inflammation.
• miR-200c-3p was upregulated in HFpEF sEVs and promoted microglial activation, while DUSP1 was identified as a target.

Conclusions:

• Cardiomyocyte sEVs carrying miR-200c-3p mediate communication to hypothalamic microglia in HFpEF.
• This sEV-mediated pathway exacerbates cardiac dysfunction via neuroinflammation and sympathetic activation.
• Targeting sEV-microglia communication presents a potential therapeutic strategy for HFpEF.