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Published on: June 15, 2018
miR-17-5p Inhibits BNIP3-Mediated Mitochondrial Autophagy to Attenuate Pathological Cardiac Fibrosis
Derong Huang1, Qing Wen1, Yuchen Su1
1Department of Cardiovascular Surgery, Affiliated Hospital of Zunyi Medical University, Guizhou, China
Background:
Cardiac fibrosis plays a critical role in the progression of chronic cardiovascular conditions, with mitochondrial dysfunction acting as a central mechanism underlying pathological myocardial fibrosis. Increasing research shows that microRNAs may modulate the fibrotic process by regulating mitochondrial function via various pathways.
Aims:
To examine the involvement of miR-17-5p in modulating mitochondrial autophagy and alleviating pathological cardiac fibrosis.
Study Design:
Combined in vivo and in vitro study.
Methods:
Expression levels of miR-17-5P and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) were measured in a mouse model of myocardial fibrosis induced by abdominal aortic constriction, as well as in cardiac fibroblasts (CFs) treated with angiotensin II. CFs were transiently transfected with a miR-17-5p mimic, the pcDNA3.1-BNIP3 plasmid, or both. Cell viability was evaluated using the CCK-8 colorimetric assay. The expression of fibrotic and autophagy-related markers was determined via quantitative real-time reverse transcription polymerase chain reaction and immunoblotting. Intracellular levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) were also assessed.
Results:
Reduced myocardial miR-17-5p expression was associated with diminished left ventricular systolic function and increased collagen accumulation in heart tissue. In vitro, angiotensin II treatment led to decreased miR-17-5p expression, upregulated BNIP3, and excessive mitochondrial autophagy-evidenced by increased ROS, lowered ATP production, and elevated fibrosis-related markers. Rescue experiments demonstrated that miR-17-5p overexpression directly targeted the 3’ untranslated region (3’-UTR) of BNIP3, significantly downregulating its expression, restoring mitochondrial balance, and decreasing collagen production. Conversely, BNIP3 overexpression counteracted the anti-fibrotic and mitochondrial-protective effects of miR-17-5p.
Conclusion:
The miR-17-5p/BNIP3 signaling pathway modulates mitochondrial autophagy in CFs and plays a key role in fibrotic remodeling. This axis may serve as a promising therapeutic target for reducing cardiac fibrosis and slowing the progression of heart failure.
Insights
MicroRNA miR-17-5p protects against cardiac fibrosis by regulating mitochondrial autophagy through the BNIP3 pathway. Restoring miR-17-5p levels alleviates fibrosis and improves heart function.
Area of Science:
- Cardiology
- Molecular Biology
- Mitochondrial Biology
Background:
- Cardiac fibrosis is a key driver of cardiovascular disease progression.
- Mitochondrial dysfunction is a central mechanism in pathological myocardial fibrosis.
- MicroRNAs are increasingly recognized for their role in modulating fibrotic processes via mitochondrial pathways.
Purpose of the Study:
- To investigate the role of miR-17-5p in regulating mitochondrial autophagy.
- To determine if miR-17-5p can alleviate pathological cardiac fibrosis.
Main Methods:
- Combined in vivo and in vitro study using mouse models and cultured cardiac fibroblasts.
- Measured miR-17-5p and BNIP3 expression, cell viability, fibrotic markers, and autophagy markers.
- Assessed intracellular reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels.
Main Results:
- Reduced miR-17-5p expression correlated with impaired cardiac function and increased fibrosis.
- Angiotensin II treatment decreased miR-17-5p, increased BNIP3, and induced excessive mitochondrial autophagy.
- miR-17-5p overexpression downregulated BNIP3, restored mitochondrial function, and reduced collagen production.
Conclusions:
- The miR-17-5p/BNIP3 pathway regulates mitochondrial autophagy in cardiac fibroblasts.
- This pathway is crucial in fibrotic remodeling and represents a potential therapeutic target for heart failure.
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