Timed use of digoxin prevents heart ischemia-reperfusion injury through a REV-ERBα-UPS signaling pathway

Area of Science:

• Cardiology
• Molecular Biology
• Chronobiology

Background:

• Myocardial ischemia-reperfusion injury (MIRI) causes severe cardiac damage, necessitating effective cardioprotective therapies.
• MIRI's severity exhibits daily fluctuations, linked to the cellular clock, particularly the nuclear receptor REV-ERBα.

Purpose of the Study:

• To investigate the cardioprotective effects of timed digoxin administration.
• To elucidate the molecular mechanisms underlying digoxin's action on REV-ERBα.

Main Methods:

• Administration of digoxin to mice and isolated cardiomyocytes.
• Assessment of REV-ERBα protein levels, ubiquitination, and proteasomal degradation.
• Investigation of the roles of heme binding, Src tyrosine-kinase, E3 ubiquitin ligases (SIAH2, PSMB5), and the proteasome.

Main Results:

• Timed digoxin administration demonstrated cardioprotection in mice.
• Dig digoxin treatment induced REV-ERBα ubiquitination and proteasomal degradation in cardiomyocytes.
• This degradation was dependent on REV-ERBα's heme-binding ability and involved SIAH2 and PSMB5.

Conclusions:

• Targeting REV-ERBα proteostasis via the ubiquitin-proteasome system is a promising cardioprotective strategy.
• Clinically approved cardiotonic steroids, like digoxin, can be used for timed prophylactic cardioprotection.