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Published on: June 15, 2018
The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1
Yuqiong Chen1, Su Li2, Yan Zhang3
1Department of Cardiology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping, Shenyang, Liaoning, 110001, PR China.
Rationale:
Myocardial infarction (MI) is a leading cause of cardiovascular mortality globally. The improvement of microvascular function is critical for cardiac repair after MI. Evidence now points to long non-coding RNAs (lncRNAs) as key regulators of cardiac remodelling processes. The lncRNA Malat1 is involved in the development and progression of multiple cardiac diseases. Studies have shown that Malat1 is closely related to the regulation of endothelial cell regeneration. However, the potential molecular mechanisms of Malat1 in repairing cardiac microvascular dysfunction after MI remain unreported.
Methods And Results:
The present study found that Malat1 is upregulated in the border zone of infarction in mouse hearts, as well as in isolated cardiac microvascular endothelial cells (CMECs). Targeted knockdown of Malat1 in endothelial cells exacerbated oxidative stress, attenuated angiogenesis and microvascular perfusion, and as a result decreased cardiac function in MI mice. Further studies showed that silencing Malat1 obviously inhibited CMEC proliferation, migration and tube formation, which was at least in part attributed to disturbed mitochondrial dynamics and activation of the mitochondrial apoptosis pathway. Moreover, bioinformatic analyses, luciferase assays and pull-down assays indicated that Malat1 acted as a competing endogenous RNA (ceRNA) for miR-26b-5p and formed a signalling axis with Mfn1 to regulate mitochondrial dynamics and endothelial functions. Overexpression of Mfn1 markedly reversed the microvascular dysfunction and CMEC injuries that were aggravated by silencing Malat1 via inhibition of excessive mitochondrial fragments and mitochondria-dependent apoptosis.
Conclusions:
The present study elucidated the functions and mechanisms of Malat1 in cardiac microcirculation repair after MI. The underlying mechanisms of the effects of Malat1 could be attributed to its blocking effects on miR-26b-5p/Mfn1 pathway-mediated mitochondrial dynamics and apoptosis.
Insights
Long non-coding RNA Malat1 promotes cardiac microvascular repair after myocardial infarction by regulating mitochondrial function and apoptosis via the miR-26b-5p/Mfn1 pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- RNA Biology
Background:
- Myocardial infarction (MI) is a major cause of death worldwide, with microvascular function crucial for cardiac repair.
- Long non-coding RNAs (lncRNAs) regulate cardiac remodeling, and Malat1 is implicated in cardiac diseases and endothelial cell regeneration.
- The specific role of Malat1 in repairing cardiac microvascular dysfunction post-MI is not fully understood.
Purpose of the Study:
- To investigate the function and molecular mechanisms of lncRNA Malat1 in cardiac microvascular repair following myocardial infarction.
- To determine if Malat1 influences endothelial cell function, mitochondrial dynamics, and apoptosis in the context of MI.
Main Methods:
- Upregulation of Malat1 in infarcted mouse hearts and cardiac microvascular endothelial cells (CMECs) was confirmed.
- Malat1 knockdown in CMECs was performed to assess its impact on angiogenesis, perfusion, and cardiac function.
- Mechanisms involving mitochondrial dynamics, apoptosis, and the miR-26b-5p/Mfn1 axis were investigated using bioinformatic and molecular assays.
Main Results:
- Malat1 upregulation was observed in MI mouse hearts and CMECs.
- Knockdown of Malat1 worsened oxidative stress, reduced angiogenesis and perfusion, and impaired cardiac function post-MI.
- Silencing Malat1 inhibited CMEC proliferation, migration, and tube formation by disrupting mitochondrial dynamics and activating apoptosis; this was linked to the Malat1/miR-26b-5p/Mfn1 pathway.
Conclusions:
- Malat1 plays a protective role in cardiac microcirculation repair after MI.
- Malat1 functions by modulating the miR-26b-5p/Mfn1 pathway, thereby regulating mitochondrial dynamics and apoptosis in endothelial cells.
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