Duo-activation of PKA and PKG by PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against proteinopathy

No current treatment is intended to target cardiac proteotoxicity or can reduce mortality of heart failure with preserved ejection fraction (HFpEF), a prevalent form of heart failure (HF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment is recently implicated in HF genesis. Activation of the cGMP-protein kinase G (PKG) or the cAMP-protein kinase A (PKA) pathways facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for the majority of PDE activities in human myocardium. Here we report the preclinical therapeutic efficacy and a new mechanism of action of PDE1 inhibition (IC86430) for cardiac proteinopathy caused by Arg120Gly missense mutant B-crystallin (CryABR120G). In mice expressing GFPdgn, an inverse reporter of UPS proteolytic activity, IC86430 treatment increased myocardial 26S proteasome activities and substantially decreased GFPdgn protein levels. Myocardial PDE1A expression was highly upregulated in CryABR120G mice. HFpEF was detected in CryABR120G mice at 4 months; IC86430 treatment initiated at this stage markedly attenuated HFpEF, substantially delayed mouse premature death, increased myocardial levels of Ser14-phosphorylated Rpn6, and reduced the steady state level of the misfolded CryAB species in these mice. In cultured cardiomyocytes, IC86430 treatment increased proteasome activities and accelerated proteasomal degradation of GFPu and CryABR120G in a PKA- and PKG- dependent manner. We conclude that PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins in cardiomyocytes and effectively treats HFpEF caused by CryABR120G; hence, PDE1 inhibition represents a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress. One Sentence SummaryPDE1 inhibition enhances proteasomal degradation of misfolded proteins in a PKA and PKG dependent manner and protects against cardiac proteinopathy and heart failure with preserved ejection fraction.