Background: Chronic low-grade inflammation is a hallmark of heart failure with preserved ejection fraction (HFpEF), contributing to maladaptive remodeling and impaired cyclic nucleotide signaling. Phosphodiesterases 1 and 2 (PDE1/2), which hydrolyze cAMP and cGMP, are emerging as inflammation-sensitive enzymes. However, their spatial and chamber-specific regulation in HFpEF remains poorly understood.
Objective: To dissect the inflammation-driven regulation of PDE1/2 in cardiovascular cells and to compare their expression and activity in the left (LV) and right ventricles (RV) in HFpEF.
Methods: We analyzed PDE1 and PDE2 expression and activity in LV and RV tissues from human myocardium from patients with HFpEF and murine ZSF1 obese rats (a validated HFpEF model). Parallel in vitro studies were conducted in human endothelial cells (HUVECs) and iPSC-derived cardiomyocytes exposed to pro-inflammatory stimuli (TNF-α, LPS, palmitate, H₂O₂). Western blotting and functional assays were used to quantify PDE levels and cyclic nucleotide degradation capacity.
Results:
PDE1 and PDE2 were significantly upregulated in the LV of both HFpEF patients and ZSF1 rats, corresponding with increased myocardial inflammation, fibrosis, and suppressed cGMP-PKG signaling. In stark contrast, the RV of the same HFpEF hearts exhibited a pronounced downregulation of both PDE1 and PDE2 expression and activity, despite evidence of inflammation, resulting in impaired stress-response signaling and altered calcium handling.
In parallel in vitro experiments, human endothelial cells (HUVECs) and iPSC-derived cardiomyocytes exposed to pro-inflammatory stimuli (TNF-α, LPS, palmitate, H₂O₂) showed consistent upregulation of PDE1 and PDE2, confirming that inflammation is a sufficient trigger for their induction. This mechanistic insight supports our in vivo findings where inflammation-rich LV tissue in HFpEF patients and ZSF1 rats showed robust PDE1/2 upregulation. In contrast, RV tissue, although also inflamed failed to mount a similar PDE response, suggesting chamber-specific differences in inflammatory signal integration or compensatory capacity. The inability of the RV to upregulate PDE1/2 may impair cyclic nucleotide signaling under stress, exacerbating right-sided dysfunction in HFpEF.
Conclusion:
This study identifies inflammation as a key upstream regulator of PDE1/2 and uncovers a novel chamber-specific divergence in PDE regulation in HFpEF. This is the first demonstration of a chamber-specific, inflammation-linked divergence in PDE1/2 regulation in HFpEF. These findings position PDE1/2 not only as readouts of inflammatory stress, but also as chamber-specific therapeutic entry points for restoring cyclic nucleotide homeostasis and improving biventricular function in HFpEF.
