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Published on: August 4, 2016
Targeting DNMT1 Attenuates Radiation-Induced Heart Disease: An Integrated Multiomic and Functional Study
Gang Wang1, Yan-Ling Li2,3, Bo-Wen Wang2,3
1The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.
Abstract:
Radiation-induced heart disease (RIHD) is a serious adverse reaction after tumor radiotherapy; its molecular mechanism is not yet clear, and there is a lack of effective treatment strategies. DNA methyltransferase 1 (DNMT1) plays crucial roles in various biological processes, but its function in RIHD remains to be explored. This study aimed to systematically elucidate the molecular map of RIHD using multiomic methods, with a focus on the specific functions and mechanisms of DNMT1 in the development of RIHD. In this study, in vivo and in vitro models of radiation-induced cardiac injury were constructed. Changes in molecular expression in cardiac tissues and cells caused by radiation were systematically analyzed through techniques such as transcriptomics and proteomics. Adeno-associated virus and lentivirus transfection techniques were used to knock down Dnmt1 expression to explore its functional role in RIHD. Multiomic analysis revealed significant activation of immune/inflammatory responses and metabolic disorders in RIHD. X-ray irradiation induced myocardial tissue and cell damage and inhibited PI3K/PDK1/AKT signaling. Moreover, radiation significantly upregulated the expression of DNMT1 in myocardial tissue and cells. Dnmt1 knockdown alleviated radiation-induced myocardial tissue and cell damage and partially reversed the inhibition of PI3K/AKT signaling. In addition, 15 proteins directly interacting with DNMT1 were identified by CO-IP and GST-pulldown assays combined with mass spectrometry, suggesting that these proteins may participate in the development of RIHD through a variety of molecular mechanisms. The results of this study revealed that DNMT1 plays a role in promoting disease progression by regulating the PI3K/AKT signaling pathway in RIHD. These findings provide a new perspective for understanding the pathogenesis of RIHD and suggest that DNMT1 may serve as a potential target for therapeutic interventions. Therefore, DNMT1 represents a promising therapeutic target for preventing RIHD.
Insights
DNA methyltransferase 1 (DNMT1) promotes radiation-induced heart disease (RIHD) by regulating the PI3K/AKT pathway. DNMT1 inhibition may offer a new therapeutic strategy for preventing RIHD.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Radiation-induced heart disease (RIHD) is a severe complication of radiotherapy with unclear mechanisms.
- DNA methyltransferase 1 (DNMT1) is implicated in various biological processes, but its role in RIHD is unexplored.
Purpose of the Study:
- To elucidate the molecular mechanisms of RIHD using multiomic approaches.
- To investigate the specific function and role of DNMT1 in RIHD development.
Main Methods:
- Construction of in vivo and in vitro models of radiation-induced cardiac injury.
- Transcriptomic and proteomic analyses to identify molecular changes.
- DNMT1 knockdown using viral vectors to assess its functional role.
- Co-immunoprecipitation and mass spectrometry to identify DNMT1 interacting proteins.
Main Results:
- Multiomic analysis revealed immune activation, inflammation, and metabolic disorders in RIHD.
- X-ray irradiation induced myocardial damage and inhibited PI3K/AKT signaling.
- Radiation upregulated DNMT1 expression; DNMT1 knockdown alleviated damage and partially restored PI3K/AKT signaling.
- 15 proteins interacting with DNMT1 were identified, suggesting diverse molecular roles.
Conclusions:
- DNMT1 promotes RIHD progression by regulating the PI3K/AKT signaling pathway.
- DNMT1 is a potential therapeutic target for preventing RIHD.
- This study provides novel insights into RIHD pathogenesis.
