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Published on: July 7, 2016

Targeting PKGIα Cys42 attenuates cardiac dysfunction in heart failure with preserved ejection fraction

Jie Su1, Yue Zhao1, Pierre Coleman1

  • 1School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.

Science Advances
|August 19, 2026
PubMed

Insights

Urolithin A activates a protective mechanism in heart failure with preserved ejection fraction (HFpEF) by modifying a specific protein. This natural compound improves heart function and reduces cardiac remodeling in HFpEF models.

Area of Science:

  • Cardiovascular Research
  • Molecular Pharmacology
  • Biochemistry

Background:

  • Heart failure with preserved ejection fraction (HFpEF) presents significant morbidity and mortality with limited therapeutic strategies.
  • Oxidation of Cys42 in cyclic guanosine monophosphate (cGMP)-dependent protein kinase Iα (PKGIα) can improve vascular and diastolic relaxation, key processes affected in HFpEF.

Purpose of the Study:

  • To investigate natural compounds with thiol reactivity as potential modulators of PKGIα for HFpEF treatment.
  • To identify novel therapeutic targets and agents for HFpEF.

Main Methods:

  • Screening of natural compounds for predicted thiol reactivity targeting PKGIα.
  • Utilizing a multihit HFpEF animal model that replicates human conditions.
  • Validation in human engineered heart tissue.

Main Results:

  • Urolithin A was identified as a novel activator of PKGIα through direct modification of Cys42.
  • Urolithin A treatment improved diastolic function and attenuated cardiac remodeling in an HFpEF model.
  • Urolithin A enhanced relaxation and contraction kinetics in human engineered heart tissue.

Conclusions:

  • Cys42 in PKGIα represents a promising therapeutic target for HFpEF.
  • Urolithin A is a previously unrecognized activator of the Cys42-PKGIα pathway, offering a potential therapeutic approach for HFpEF.

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