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

Hanming Zhang, Bo Pan, Penglong Wu, Nirmal Parajuli, Mark D. Rekhter, Alfred L. Goldberg, Xuejun Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 26S proteasome activities and UPS proteolytic function in mice. Mice with CryABR120Gbased 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 CryABR120G, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.

Original languageEnglish (US)
Article numberaaw5870
JournalScience Advances
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2019

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ejection
degradation
proteins
mice
heart diseases
myocardium
phosphorylation
pulse detonation engines
mortality
impairment
nucleotides
promotion
activation
cells

ASJC Scopus subject areas

  • General
  • Physics and Astronomy (miscellaneous)

Cite this

PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy. / Zhang, Hanming; Pan, Bo; Wu, Penglong; Parajuli, Nirmal; Rekhter, Mark D.; Goldberg, Alfred L.; Wang, Xuejun.

In: Science Advances, Vol. 5, No. 5, aaw5870, 01.01.2019.

Research output: Contribution to journalArticle

Zhang, Hanming ; Pan, Bo ; Wu, Penglong ; Parajuli, Nirmal ; Rekhter, Mark D. ; Goldberg, Alfred L. ; Wang, Xuejun. / PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy. In: Science Advances. 2019 ; Vol. 5, No. 5.
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