Exosomes from young healthy human plasma ameliorate sepsis-induced cardiomyopathy by inhibiting ferroptosis via the miR-3130-3p/LPCAT3 axis.

BACKGROUND

Sepsis-induced cardiomyopathy (SICM) is one of the leading causes of mortality in sepsis patients, and currently, there are no effective treatments available. Ferroptosis has been proven to play a critical role in SICM. Exosomes from the young healthy human plasma (exosomesYoung) were shown to improve cardiac fibrosis post-myocardial infarction in our previous studies. However, their role in SICM remains unclear.

METHODS

We established in vivo and in vitro models of SICM induced by lipopolysaccharide (LPS). The severity of cardiac and cardiomyocyte injury was evaluated through echocardiography, histological analysis, measurements of myocardial injury markers, and cell viability assays. Improvements in SICM via inhibition of ferroptosis by exosomesYoung were demonstrated by assessing ferroptosis-related indicators, including Fe2+, malondialdehyde (MDA), Liperfluo (LPO) levels, PTGS2 expression, and mitochondrial structural integrity.

RESULTS

In this study, we demonstrated that exosomesYoung significantly improved cardiac function and mitigated morphological damage in the hearts of mice with SICM. ExosomesYoung also enhanced the viability of LPS-induced cardiomyocytes, reduced levels of lipid peroxides and ferroptosis biomarkers, and suppressed ROS production, mitochondrial membrane potential reduction, and mitochondrial ultrastructural damage. Mechanistically, high-throughput sequencing analysis followed by qRT-PCR validation identified miR-3130-3p as a key effector molecule. Upregulation of miR-3130-3p mimicked the therapeutic effects of exosomesYoung on LPS-induced cardiac injury and mediated the cardioprotective role of exosomesYoung against ferroptosis in SICM. Further, target gene prediction using databases and validation with a dual-luciferase reporter assay confirmed LPCAT3 as the direct target gene of miR-3130-3p in inhibiting ferroptosis. Overexpression of LPCAT3 could reverse the protective effects of miR-3130-3p on LPS-induced SICM.

CONCLUSIONS

In summary, these findings reveal for the first time that exosomesYoung improve SICM by inhibiting ferroptosis via miR-3130-3p targeting LPCAT3. This study provides novel insights into the potential of exosomesYoung as promising cardioprotective candidates for patients with SICM.