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Updated: May 12, 2026
Digital PCR for Quantifying Circulating MicroRNAs in Acute Myocardial Infarction and Cardiovascular Disease
Published on: July 3, 2018
CircClint1/miR-378b/NPDC1 axis: A novel therapeutic target and biomarker for myocardial infarction
Xin Zhang1, Xingyu Zhu1, Zijian Dang1
1Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China.
Insights
A novel molecular pathway involving circClint1, miR-378b, and NPDC1 significantly worsens heart damage after myocardial infarction (MI). Targeting this axis offers a promising therapeutic strategy for improving cardiovascular outcomes post-MI.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genomics
Background:
- Myocardial infarction (MI) leads to ischemic cardiomyopathy due to limited treatment options for adverse remodeling.
- Current interventions struggle to halt the progression of heart damage post-MI.
Purpose of the Study:
- To identify key molecular mediators of adverse remodeling in a murine myocardial infarction model.
- To elucidate the functional role of the circClint1/miR-378b/NPDC1 axis in post-MI cardiac injury.
Main Methods:
- Whole-transcriptome sequencing and bioinformatic analysis in a murine MI model.
- Luciferase reporter assays, RNA pull-down, Western blot, and immunofluorescence.
- AAV9-mediated gene delivery for in vivo functional studies and siRNA for in vitro validation.
Main Results:
- circClint1 was identified as a crucial upregulated mediator in the infarcted microenvironment.
- circClint1 acts as a ceRNA for miR-378b, leading to increased NPDC1 protein accumulation.
- NPDC1 elevation exacerbates post-MI damage via cardiomyocyte apoptosis, fibrosis, and impaired microcirculation.
- NPDC1 silencing attenuated hypoxia-induced stress and improved cell viability in cardiomyocytes.
Conclusions:
- The circClint1/miR-378b/NPDC1 axis is a key detrimental driver in post-MI progression.
- NPDC1 plays a critical role in coordinating cardiomyocyte death and impaired revascularization.
- This axis represents a potential therapeutic target for mitigating myocardial injury and improving long-term cardiovascular outcomes.
Abstract:
Myocardial infarction (MI) remains a leading cause of global morbidity, often progressing to irreversible ischemic cardiomyopathy due to the limitations of current pharmacological interventions in arresting adverse remodeling. Here, we combined whole-transcriptome sequencing with bioinformatic prioritization in a murine MI model to identify circClint1 as a pivotal, upregulated mediator within the infarcted microenvironment. Mechanistically, luciferase reporter assays and RNA pull-down confirmed that circClint1 functions as a competitive endogenous RNA (ceRNA) for miR-378b, thereby sequestering the miRNA and preventing the targeted degradation of its downstream effector, NPDC1. Notably, both in vivo Western blot and immunofluorescence revealed that ischemic stress triggers a dramatic and spatiotemporal accumulation of NPDC1 protein, particularly within the cytoplasm of peri-infarct cardiomyocytes. Functionally, we established an AAV9-mediated myocardial-specific overexpression model to evaluate the pathological consequences of sustained NPDC1 elevation. Our results demonstrated that NPDC1 accumulation significantly exacerbates post-infarction damage by promoting TUNEL-positive cardiomyocyte apoptosis, intensifying fibrotic remodeling, and impairing the myocardial microcirculation. Conversely, siRNA-mediated genetic silencing of NPDC1 in HL-1 cardiomyocytes effectively attenuated hypoxia-induced oxidative stress, preserved mitochondrial membrane potential, and improved cell viability. Collectively, this study provides definitive evidence that the circClint1/miR-378b/NPDC1 axis is a master detrimental driver of post-MI progression. By elucidating the multi-dimensional role of NPDC1 in coordinating cell death and impaired revascularization, our findings identify this axis as a promising therapeutic target for mitigating myocardial injury and improving long-term cardiovascular outcomes.
