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bioRxiv · 10.1101/2025.09.30.679675

PDE3A2 modRNA Fine-Tunes Nuclear cAMP Microdomains and Reverses Pathological Cardiac Hypertrophy

Xiang, W.·Lian, M.·Guan, Q.·Sun, X.·Li, S.·Lu, H.·Qin, G.·Xiang, Y. K.·Ni, H.·Wang, Y.
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Abstract

Pathological cardiac hypertrophy (PCH) is a precursor to heart failure, driven in part by dysregulated nuclear-localized cAMP (NLS-cAMP) signaling. Phosphodiesterase 3A2 (PDE3A2) is a key regulator of this nuclear cAMP microdomain, yet its selective modulation remains challenging. Here, we developed PDE3A2-modified RNA (PDE3A2-modRNA) to restore nuclear PDE3A2 levels and tested its efficacy in an angiotensin II-induced PCH model. Subcellular FRET imaging revealed that PCH hearts exhibit hyperactive NLS-cAMP due to PDE3A2 depletion. PDE3A2-modRNA selectively reduced NLS-cAMP without altering cytosolic cAMP, demonstrating precise microdomain regulation. In vivo, PDE3A2-modRNA improved cardiac function, attenuated hypertrophy and fibrosis, and shifted transcriptional programs toward physiological remodeling. Single-nucleus transcriptomics and immune profiling further revealed reduced oxidative stress and an improved cardiac microenvironment. These findings highlight PDE3A2-modRNA as a novel gene therapy that selectively restores nuclear cAMP homeostasis, reversing PCH-promoting transcriptional programs while preserving physiological cAMP signaling in cytosolic microdomains.

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Xiang, W., Lian, M., Guan, Q., Sun, X., Li, S., Lu, H., Qin, G., Xiang, Y. K., Ni, H., Wang, Y.. 2025-10-02. PDE3A2 modRNA Fine-Tunes Nuclear cAMP Microdomains and Reverses Pathological Cardiac Hypertrophy. https://doi.org/10.1101/2025.09.30.679675

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