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Published on: January 10, 2025
MiR-135b protects cardiomyocytes from infarction through restraining the NLRP3/caspase-1/IL-1β pathway
Anqi Li1, Yahan Yu1, Xueying Ding1
1Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, PR China.
Background:
Myocardial infarction (MI) is the most common cause of cardiovascular morbidity and mortality worldwide. Despite the identification of many pathogenic genes associated with MI, the underlying molecular mechanisms remain poorly understood. MicroRNAs (miRNAs, miRs), which regulate target genes at the post-transcriptional level, play a significant role in the regulation of cardiovascular diseases such as MI. Pyroptosis is a caspase-1-dependent pro-inflammatory programmed cell death (PCD) mechanism. The role of pyroptosis in several diseases associated with various miRNAs has been studied extensively. Meanwhile, the role of NOD-like receptor-containing pyrin 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) pathway in cardiac diseases has also been more recognized.
Methods:
We established a mice MI model which ligated with the left anterior descending coronary artery and a cardiomyocytes injury model treated by hydrogen peroxide (H2O2) to detect the expressions of miR-135b and NLRP3/caspase-1/IL-1β pathway. Then miR-135b mimic, agomir-135b, and α-MHC-miR-135b transgenic mice were used to evaluate the effects of miR-135b overexpression.
Result:
We demonstrated that miR-135b was downregulated after cardiomyocytes injury both in vivo and in vitro. Pyroptosis pathway was also activated. MiR-135b overexpression remarkably restored impaired cardiac function and attenuated the upregulation of NLRP3/caspase-1/IL-1β pathway.
Conclusions:
The present findings shed light on the protective role of miR-135b in MI mediated by the inhibition of the NLRP3/caspase-1/IL-1β pathway.
Insights
MicroRNA-135b (miR-135b) protects against myocardial infarction (MI) by inhibiting the NLRP3 inflammasome pathway. Overexpression of miR-135b improved cardiac function and reduced inflammation in MI models.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Death Mechanisms
Background:
- Myocardial infarction (MI) is a leading cause of death globally, with complex underlying molecular mechanisms.
- MicroRNAs (miRNAs) regulate gene expression and are implicated in cardiovascular diseases like MI.
- Pyroptosis, a pro-inflammatory cell death pathway involving NLRP3 inflammasome, is increasingly recognized in cardiac pathology.
Purpose of the Study:
- To investigate the role of miR-135b in myocardial infarction.
- To explore the relationship between miR-135b and the NLRP3/caspase-1/IL-1β pathway in cardiac injury.
- To evaluate the therapeutic potential of miR-135b in a mouse model of MI.
Main Methods:
- Established mouse models of myocardial infarction and in vitro models of cardiomyocyte injury.
- Assessed the expression levels of miR-135b and the NLRP3/caspase-1/IL-1β pathway components.
- Utilized miR-135b mimics, agomir-135b, and transgenic mice to study the effects of miR-135b overexpression.
Main Results:
- miR-135b was significantly downregulated in cardiomyocytes following injury, both in vivo and in vitro.
- Pyroptosis pathway activation was observed concurrently with miR-135b downregulation.
- Overexpression of miR-135b improved cardiac function and attenuated the activation of the NLRP3/caspase-1/IL-1β pathway.
Conclusions:
- miR-135b plays a protective role in myocardial infarction.
- The protective effect of miR-135b is mediated through the inhibition of the NLRP3/caspase-1/IL-1β inflammasome pathway.
- miR-135b represents a potential therapeutic target for managing MI.
