Protective effect of Adropin on sepsis-induced cardiomyopathy.

BACKGROUND AND AIM: Sepsis-induced cardiomyopathy (SIMD) is linked to higher mortality rates in patients with sepsis, yet there are currently no targeted therapies available for this condition. Adropin, known for its anti-inflammatory, antioxidant, and anti-apoptotic properties, has attracted significant interest in relation to cardiovascular diseases. This research aims to clarify the protective role of adropin in septic cardiomyopathy and to explore the mechanisms behind its effects.

METHODS

This study demonstrates that adropin provides a protective effect against septic cardiomyopathy in both cellular and mouse models. Differential expression analysis of the energy homeostasis-associated gene (ENHO) was initially performed using datasets from the Gene Expression Omnibus (GEO)database related to septic cardiomyopathy. This was followed by validation in Lipopolysaccharide (LPS)-induced mouse model of myocardial injury. Cardiac function and myocardial pathological changes were assessed using ultrasonography and hematoxylin-eosin (HE) staining techniques. Molecular-level analysis of inflammation, apoptosis, and oxidative stress-related proteins were conducted using quantitative real-time PCR (qRT-PCR) and Western blot methodologies. Dihydroethidium (DHE) staining and flow cytometry were employed to evaluate oxidative stress levels in mouse myocardial tissues and cells. Finally, rescue experiments were conducted at the cellular level using the nuclear factor erythroid-2 (Nrf2) inhibitor ML385 to investigate the underlying mechanistic pathways.

RESULTS

Adropin expression was significantly decreased in septic cardiomyopathy compared to the control group. In contrast to the LPS group, the administration of exogenous adropin markedly improved cardiac function, reduced myocardial edema, and decreased inflammatory cell infiltration. In both murine and cellular models, adropin treatment substantially down-regulated the pro-apoptotic protein bax while up-regulating the anti-apoptotic protein bcl-2. Furthermore, at the inflammatory level, adropin administration significantly diminished the burden of inflammatory factors such as TNF-α, IL-6, and IL-1β compared to the LPS model group. Regarding oxidative stress, adropin administration notably reduced the levels of reactive oxygen species (ROS) and increased the abundance of antioxidant stress proteins NQO1, GPX1, and Nrf2. when compared to the LPS model group. However, in the presence of the NRF2 inhibitor ML385, the levels of NQO1, GPX1, and Nrf2 were decreased in the LPS + adropin+ML385 group compared to the LPS + adropin group.

CONCLUSION

Adropin exerts protective effects in septic cardiomyopathy through anti-inflammatory, anti-apoptotic, and antioxidative mechanisms. It mitigates the LPS-induced myocardial injury by enhancing intracellular antioxidant protein expression via activation of the Nrf2/antioxidant response element (ARE) signaling pathway. In conclusion, adropin holds considerable therapeutic potential for addressing sepsis-induced cardiomyopathy in clinical practice.