Publication Date:
2019
Description:
〈p〉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 (PKA) 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 26〈i〉S〈/i〉 proteasome activities and UPS proteolytic function in mice. Mice with CryAB〈sup〉R120G〈/sup〉-based proteinopathy develop HFpEF and show increased myocardial PDE1A expression. PDE1 inhibition markedly attenuates HFpEF, improves mouse survival, increases PKA-mediated proteasome phosphorylation, and reduces myocardial misfolded CryAB. Therefore, PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins and treats HFpEF caused by CryAB〈sup〉R120G〈/sup〉, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.〈/p〉
Electronic ISSN:
2375-2548
Topics:
Natural Sciences in General
