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.