Do hypoxia-conditioned hMSC-derived EVs reduce cardiac hypertrophy in preclinical models compared to normoxia-conditioned EVs?
Hypoxia-conditioned hMSC-derived EVs enriched with DJ-1 show potential as a novel therapeutic agent for cardiac hypertrophy by suppressing mitochondrial dysfunction and preventing ATRAP degradation.
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.
Lu et al. (Fri,) studied this question.