Cereblon contributes to cardiac dysfunction by degrading Cav1.2α
| العنوان: | Cereblon contributes to cardiac dysfunction by degrading Cav1.2α |
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| المؤلفون: | Nammi Park, Jubert Marquez, Trong Kha Pham, Tae Hee Ko, Jae Boum Youm, Min Kim, Seung Hak Choi, Jiyoung Moon, Jessa Flores, Kyung Soo Ko, Byoung Doo Rhee, Ippei Shimizu, Tohru Minamino, Jae Du Ha, Jong Yeon Hwang, Seung Joo Yang, Chul-Seung Park, Hyoung Kyu Kim, Jin Han |
| المصدر: | European Heart Journal. 43:1973-1989 |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Heart Failure, Mice, Ubiquitin-Protein Ligases, Ubiquitination, Animals, Humans, Stroke Volume, Cardiology and Cardiovascular Medicine, Adaptor Proteins, Signal Transducing |
| الوصف: | Aims Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. Methods and results Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN−/−) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (I CaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased I CaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced I CaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Conclusion Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics. |
| تدمد: | 1522-9645 0195-668X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9c325a8da91ba2231912ccc74c06466 https://doi.org/10.1093/eurheartj/ehac072 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a9c325a8da91ba2231912ccc74c06466 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15229645 0195668X |
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