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Published on: December 9, 2013
Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury
Sunhye Shin1, Jung-Won Choi2, Hanbyeol Moon3
1Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul 03722, Republic of Korea; Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea.
Abstract:
Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease.
Insights
MicroRNA-105 (miR-105) suppresses programmed cell death pathways, including apoptosis and necroptosis, in heart cells. This finding suggests miR-105 as a potential therapeutic target for protecting against heart damage after myocardial infarction.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Death Pathways
Background:
- Apoptosis and necroptosis signaling are linked to acute heart injury.
- MicroRNA-105 (miR-105) is dysregulated in myocardial infarction (MI).
Purpose of the Study:
- To investigate miR-105's role in regulating RIP3/p-MLKL-dependent necroptosis and BNIP3-dependent apoptosis.
- To assess miR-105's therapeutic potential in myocardial infarction.
Main Methods:
- Utilized H9c2 cells under hypoxic conditions and rat models of myocardial infarction.
- Investigated the expression of RIP3, p-MLKL, and BNIP3.
- Administered miR-105 to MI rat hearts and evaluated infarct size.
Main Results:
- Hypoxia enhanced RIP3/p-MLKL necroptosis and BNIP3 apoptosis signaling in H9c2 cells.
- miR-105 treatment suppressed these pathways in H9c2 cells.
- miR-105 directly inhibits RIP3 and BNIP3 expression.
- In vivo, miR-105 reduced infarct size in MI rat hearts.
Conclusions:
- miR-105 suppresses both necroptotic and apoptotic cell death pathways.
- miR-105 acts at multiple levels to inhibit cardiomyocyte death post-MI.
- miR-105 represents a promising therapeutic strategy for cardioprotection in ischemic heart disease.
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