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Published on: August 10, 2018
Tripartite motif 16 mitigates endotoxemia-induced cardiac dysfunction via the Cav-1/Src/YAP signaling axis in mice
Bing Han1, Kaina Zhang1, Yating Li1
1Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
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.
Insights
Tripartite Motif 16 (TRIM16) protects against septic cardiomyopathy by regulating the Cav-1/Src/YAP/Nrf2 pathway. Enhancing TRIM16 activity mitigates cardiac dysfunction and oxidative stress in sepsis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Sepsis Research
Background:
- Septic cardiomyopathy (SIC) is a severe sepsis complication with limited treatments.
- The role of Tripartite Motif 16 (TRIM16) in SIC is currently unknown.
Purpose of the Study:
- To investigate the role and mechanism of TRIM16 in septic cardiomyopathy.
- To explore TRIM16 as a potential therapeutic target for SIC.
Main Methods:
- TRIM16 expression was manipulated in neonatal rat cardiomyocytes and a mouse sepsis model (CLP).
- Cardiac function, oxidative stress, inflammation, apoptosis, and signaling pathways (Cav-1, Src, YAP, Nrf2/HO-1) were assessed.
Main Results:
- TRIM16 was upregulated in septic cardiomyocytes.
- TRIM16 deficiency worsened sepsis-induced cardiac injury, while overexpression protected against it.
- TRIM16 promoted Cav-1 degradation, activating Src/YAP and the Nrf2/HO-1 antioxidant pathway.
Conclusions:
- TRIM16 plays a protective role in SIC through the Cav-1/Src/YAP/Nrf2 pathway.
- TRIM16 represents a promising therapeutic target for mitigating sepsis-induced cardiac dysfunction.
