Cereblon contributes to cardiac dysfunction by degrading Cav1.2α
Nammi Park1, Jubert Marquez1, Trong Kha Pham1
1Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 614-735, Republic of Korea.
European Heart Journal
|February 22, 2022
Summary
Cereblon (CRBN) degrades Cav1.2α, worsening heart failure. Reducing CRBN levels or using CRBN degraders enhances cardiac function and may treat heart failure with reduced ejection fraction (HFrEF).
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- E3 Ubiquitin Ligase Biology
Background:
- Cereblon (CRBN) targets proteins for degradation via the E3 ubiquitin ligase complex.
- L-type voltage-dependent Ca2+ channel (LTCC) dysfunction is key in heart failure with reduced ejection fraction (HFrEF).
- The role of CRBN in regulating LTCC Cav1.2α during cardiac dysfunction is not well understood.
Purpose of the Study:
- To investigate the role of CRBN in HFrEF.
- To explore CRBN's direct regulatory role in Cav1.2α activity.
- To assess CRBN as a therapeutic target for myocardial dysfunction.
Main Methods:
- Analysis of cardiac tissues from HFrEF patients and controls.
- In vivo and ex vivo studies using CRBN knockout mouse models.
- Investigation of CRBN-Cav1.2α interaction using genetic and pharmacological approaches, including a PROTAC degrader (TD-165).
Main Results:
- Increased CRBN levels were observed in HFrEF cardiac tissues.
- CRBN knockout mice showed enhanced cardiac contractility and LTCC current (ICaL).
- CRBN directly interacts with Cav1.2α, promoting its ubiquitination and degradation, thereby reducing ICaL. Depletion of CRBN increased ICaL and protected against cardiomyopathy.
Conclusions:
- Cereblon selectively degrades Cav1.2α, contributing to cardiac dysfunction in HFrEF.
- Reducing CRBN levels or targeting CRBN degradation presents a promising therapeutic strategy for HFrEF.
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