Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Proteomics

Background:

• Heart failure (HF) prevalence is increasing despite treatment advances.
• The role of Protein Phosphatase 1 (PP1) in HF pathogenesis is unclear.
• Previous studies focused on PP1 catalytic subunit (PP1c), neglecting its interactors.

Purpose of the Study:

• To define the cardiac PP1 interactome.
• To test if the PP1 interactome rearranges during HF progression.
• To identify specific PP1c interactors associated with HF.

Main Methods:

• Induction of HF in mice via transverse aortic constriction.
• Affinity purification of PP1c and mass spectrometry to identify interactors.
• Knockdown of PP1 regulatory subunit 7 (Ppp1r7) and calcium imaging.

Main Results:

• Identified 71 cardiac and 98 HeLa PP1c interactors, forming the largest PP1 interactome dataset.
• Nine PP1c interactors, including Ppp1r7, showed altered binding associated with HF progression.
• Cardiac Ppp1r7 knockdown caused cardiac dysfunction and disrupted calcium release.

Conclusions:

• The PP1 interactome undergoes significant rearrangement during HF progression.
• Nine key PP1 interactors associated with HF progression are potential therapeutic targets.
• Ppp1r7 may act as a molecular sponge regulating the PP1 interactome in HF.