Abstract

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.