Tripartite motif 16 mitigates endotoxemia-induced cardiac dysfunction via the Cav-1/Src/YAP signaling axis in mice.

BACKGROUND

Septic cardiomyopathy (SIC) is a life-threatening complication of sepsis with limited therapeutic options. Tripartite Motif 16 (TRIM16), an E3 ubiquitin ligase, is implicated in cellular stress responses, but its role in SIC remains unknown.

METHODS

In neonatal rat cardiomyocytes (NRCMs) and a murine cecal ligation and puncture (CLP)-induced sepsis model, we manipulated TRIM16 expression using small interfering RNA (siRNA), plasmids, or adeno-associated virus (AAV9)-mediated gene delivery. Cardiac function, injury markers, oxidative stress, inflammation, apoptosis, calcium handling, lysosomal function, and autophagy were assessed. Mechanistic studies focused on caveolin-1 (Cav-1) ubiquitination, non-receptor tyrosine kinase (Src)/yes-associated protein (YAP) activation, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.

RESULTS

TRIM16 expression was markedly upregulated in cardiomyocytes under septic conditions. Knockdown of TRIM16 exacerbated lipopolysaccharide (LPS)-induced cardiomyocyte injury, amplifying oxidative stress, inflammation, apoptosis, calcium dysregulation, lysosomal dysfunction, and impaired autophagy. In contrast, TRIM16 overexpression significantly attenuated cardiac dysfunction and injury in CLP-challenged mice. Mechanistically, TRIM16 directly promoted ubiquitination and degradation of Cav-1, which relieved Cav-1-mediated inhibition of Src kinase (increased p-Src Y416 and decreased p-Src Y527). This led to YAP phosphorylation at Y357, nuclear translocation, and subsequent activation of the Nrf2/HO-1 antioxidant pathway, thereby mitigating oxidative stress and restoring redox homeostasis.

CONCLUSIONS

This study identifies a previously unrecognized protective role for TRIM16 in SIC via the novel Cav-1/Src/YAP/Nrf2 signaling axis. By enhancing TRIM16 activity, oxidative stress and cardiac dysfunction are mitigated, positioning TRIM16 as a promising therapeutic target for SIC.