Small extracellular vesicle-mediated adipocyte-cardiomyocyte crosstalk exacerbates heart failure with preserved ejection fraction.

Resection or transplantation of visceral adipose tissue (VAT) blunted or exacerbated HFpEF phenotypes in mice, respectively, establishing a causal relationship between VAT and HFpEF pathogenesis.

• HFpEF was induced in male C57BL/6N mice using a high-fat diet combined with N-omega-nitro-l-arginine methyl ester (L-NAME)
• Surgical removal of VAT reduced HFpEF phenotypes, while transplantation of VAT from HFpEF mice exacerbated the condition
• These experiments established a directional, causal link between adipose tissue and cardiac dysfunction in HFpEF

VAT from HFpEF mice displayed greater weight and secreted more small extracellular vesicles (sEVs) than VAT from chow-fed control mice.

• HFpEF mice exhibited increased VAT mass compared to chow-fed mice
• sEV secretion from VAT was elevated in the HFpEF condition compared to controls
• This suggested that VAT-derived sEVs could serve as mediators of adipose-to-cardiac signaling in the context of HFpEF

Systemic inhibition of sEV secretion or VAT-specific knockdown of Rab27b protected against HFpEF phenotypes in mice.

• Rab27b is described as 'an indispensable GTPase for sEV secretion'
• VAT-specific knockdown of Rab27b reduced sEV release from adipose tissue and attenuated HFpEF phenotypes
• Systemic pharmacological inhibition of sEV secretion also conferred protection against HFpEF
• These findings implicated sEV secretion from VAT as a mechanistically important pathway in HFpEF progression

miR-295-3p was identified within VAT-derived sEVs as a mediator of the VAT-heart axis that impairs cardiac autophagy by binding to Ulk1 mRNA.

• Discovery-driven experiments identified miR-295-3p as a cargo within sEVs secreted by VAT in HFpEF
• miR-295-3p impaired cardiac autophagy through direct binding to Ulk1 mRNA
• miR-295-3p antagomir treatment mitigated HFpEF phenotypes in mice
• Neonatal mouse cardiomyocytes (NMCMs) showed blunted autophagic flux after treatment with plasma sEVs from HFpEF mice

HFpEF patients displayed downregulated cardiac ULK1 expression and reduced autophagy compared with healthy individuals.

• Human cardiac tissue from HFpEF patients was compared to tissue from healthy individuals
• Cardiac ULK1 protein/mRNA levels were reduced in HFpEF patients relative to healthy controls
• Markers of cardiac autophagy were also downregulated in HFpEF patients
• These human data corroborated the mechanistic findings observed in the mouse HFpEF model

Restoration of cardiac autophagy via rapamycin treatment or AAV-9-mediated ULK1 overexpression attenuated HFpEF phenotypes in mice.

• Rapamycin, an mTOR inhibitor that activates autophagy, was used to restore autophagic flux in HFpEF mice
• ULK1 overexpression was delivered using AAV-9 vectors to specifically restore cardiac ULK1 levels
• Both interventions attenuated HFpEF phenotypes, confirming that impaired cardiac autophagy downstream of miR-295-3p/ULK1 is functionally important
• These results support ULK1 and cardiac autophagy as therapeutic targets in HFpEF