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Extracellular vesicles DJ-1 derived from hypoxia-conditioned hMSCs alleviate cardiac hypertrophy by suppressing
Yao Lu1, Jian Zhang2, Bing Han3
1Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Guangzhou Road 300, Nanjing 210029, PR China; Department of Cardiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Nanjing Medical University, No.199 Jiefang South Road, Xuzhou 221009, PR China.
Insights
Hypoxia-conditioned extracellular vesicles (Hypo-EVs) show greater potential in treating cardiac hypertrophy than normoxia-conditioned EVs. Hypo-EVs contain PARK7/DJ-1, which alleviates mitochondrial dysfunction and inhibits key pathways involved in cardiac remodeling.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Extracellular Vesicle Therapeutics
Background:
- Cardiac hypertrophy is a pathological remodeling process in cardiovascular diseases with no effective treatment.
- Human mesenchymal stem cells (hMSCs)-derived extracellular vesicles (EVs) are a promising therapeutic strategy for cardiac diseases.
Purpose of the Study:
- To compare the inhibitory effects of normoxia-conditioned hMSC-EVs (Nor-EVs) and hypoxia-conditioned hMSC-EVs (Hypo-EVs) on cardiac hypertrophy.
- To identify the key protein responsible for the enhanced therapeutic effect of Hypo-EVs.
Main Methods:
- Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (Ang II).
- A mouse model of transverse aortic constriction (TAC) was used.
- Quantitative proteomics identified differential proteins between Nor-EVs and Hypo-EVs.
Main Results:
- Hypo-EVs demonstrated a significantly greater inhibitory effect on cardiac hypertrophy compared to Nor-EVs.
- Parkinson disease protein 7 (PARK7/DJ-1) was identified as a key protein enriched in Hypo-EVs.
- DJ-1 alleviated mitochondrial dysfunction and reduced mitochondrial reactive oxygen species (mtROS) by inhibiting proteasome subunit beta type 10 (PSMB10) and AT1R-associated protein (ATRAP) degradation.
Conclusions:
- Hypoxia-conditioned hMSC-EVs show enhanced therapeutic potential for cardiac hypertrophy.
- DJ-1 plays a crucial role in the anti-hypertrophic effects of Hypo-EVs.
- DJ-1's mechanism involves inhibiting PSMB10 and regulating AT1R signaling pathways.
Background:
As a pathological myocardial remodeling process in a variety of cardiovascular diseases, cardiac hypertrophy still has no effective treatment. Human mesenchymal stem cells (hMSCs) derived extracellular vesicles (EVs) has been recognized as a promising treatment strategy for cardiac disease.
Methods:
In this study, the inhibitory effects on cardiac hypertrophy are compared between normoxia-conditioned hMSC-derived EVs (Nor-EVs) and hypoxia-conditioned hMSC-derived EVs (Hypo-EVs) in neonatal rat cardiomyocytes (NRCMs) after angiotensin II (Ang II) stimulation and in a mouse model of transverse aortic constriction (TAC).
Results:
We demonstrate that Hypo-EVs exert an increased inhibitory effect on cardiac hypertrophy compared with Nor-EVs. Parkinson disease protein 7 (PARK7/DJ-1) is identify as a differential protein between Nor-EVs and Hypo-EVs by quantitative proteomics analysis. Results show that DJ-1, which is rich in Hypo-EVs, alleviates mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (mtROS) production as an antioxidant. Mechanistic studies demonstrate for the first time that DJ-1 may suppress cardiac hypertrophy by inhibiting the activity of proteasome subunit beta type 10 (PSMB10) through a direct physical interaction. This interaction can inhibit angiotensin II type 1 receptor (AT1R)-mediated signaling pathways resulting in cardiac hypertrophy through alleviating ubiquitination degradation of AT1R-associated protein (ATRAP).
Conclusions:
When taken together, our study suggests that Hypo-EVs have significant potential as a novel therapeutic agent for the treatment of cardiac hypertrophy.
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