PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy.

No current treatment targets cardiac proteotoxicity or can reduce mortality of heart failure (HF) with preserved ejection fraction (HFpEF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment contributes to HF. Activation of cAMP-dependent protein kinase or cGMP-dependent protein kinase (PKG) facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for most PDE activities in human myocardium. We report that PDE1 inhibition (IC86430) increases myocardial 26S proteasome activities and UPS proteolytic function in mice. Mice with CryAB^R120G-based proteinopathy develop HFpEF and show increased myocardial PDE1A expression. PDE1 inhibition markedly attenuates HFpEF, improves mouse survival, increases proteasome phosphorylation, and reduces myocardial misfolded CryAB. Therefore, PDE1 inhibition induces and PKG-mediated promotion of proteasomal degradation of misfolded proteins and treats HFpEF caused by CryAB^R120G, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.

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