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Published on: May 10, 2024
EGLN1 inhibition reverses angiogenesis impairment in hyperglycemia by activating autophagy
Fengli Hu1, Zheng Li1, Ying Li1
1Cardiology department, Second Hospital of Hebei Medical University, Shijiazhuang, China.
Insights
Diabetic cardiomyopathy impairs blood vessel growth in the heart. Inhibiting EGLN1 protein activates cell repair, offering a new therapeutic target for diabetic heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Diabetes Research
Background:
- Cardiovascular complications are the leading cause of mortality in diabetes mellitus (DM).
- Diabetic cardiomyopathy (DCM) presents a unique challenge, characterized by diastolic dysfunction, hypertrophy, and fibrosis, with impaired myocardial angiogenesis contributing to poor outcomes.
- Current therapies for restoring angiogenesis in DCM are limited.
Purpose of the Study:
- To identify novel molecular targets for treating DCM.
- To investigate the role of egl-9 family hypoxia inducible factor 1 (EGLN1) in myocardial angiogenesis in DCM.
- To explore the potential of EGLN1 inhibition as a therapeutic strategy.
Main Methods:
- Bioinformatic analysis of public databases to identify differentially expressed genes in DCM.
- Establishment of a diabetic mouse model and hyperglycemic endothelial cell cultures.
- Assessment of EGLN1 expression, angiogenesis, and autophagy markers (LC3-II/LC3-I, P62).
Main Results:
- EGLN1 was significantly upregulated in diabetic mice and correlated with impaired angiogenesis.
- EGLN1 inhibition in vitro attenuated high glucose-induced endothelial dysfunction.
- EGLN1 inhibition activated autophagy pathways, indicated by increased LC3-II/LC3-I ratios and decreased P62 levels.
Conclusions:
- EGLN1 is a novel regulator of myocardial angiogenesis in diabetic cardiomyopathy.
- Inhibition of EGLN1 ameliorates high glucose-induced endothelial dysfunction by activating autophagy.
- Targeting EGLN1 and activating autophagy presents a potential therapeutic avenue for diabetic cardiovascular complications.
Abstract:
Cardiovascular complications have emerged as the predominant cause of mortality in diabetes mellitus (DM), with diabetic cardiomyopathy (DCM) representing a critical clinical challenge due to its distinct pathogenesis independent of coronary artery disease or hypertension. DCM is characterized by left ventricular diastolic dysfunction, hypertrophy, and fibrosis, with impaired myocardial angiogenesis contributing to adverse cardiovascular outcomes. Despite this, targeted therapies for angiogenesis restoration in DCM remain elusive. Through bioinformatic analysis of public databases, we identified egl-9 family hypoxia inducible factor 1 (EGLN1) as a differentially expressed gene in both preclinical DCM models and clinical specimens. To validate its role, we established mice model of diabetes and corresponding endothelial cells cultures under hyperglycemic conditions. Results demonstrated significant upregulation of EGLN1 in diabetic mice, correlating with angiogenesis impairment. Intriguingly, EGLN1 inhibition attenuated high glucose-induced endothelial dysfunction by activating autophagy pathways, as evidenced by increased LC3-II/LC3-I ratios and decreased P62 levels. These findings unveil EGLN1 as a novel regulator of myocardial angiogenesis in DCM, proposing autophagy activation as a potential therapeutic strategy to ameliorate diabetic cardiovascular complications. This study provides the first evidence linking EGLN1 dysregulation to angiogenesis defects in DCM, offering insights for targeted intervention development.
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