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Pleiotropic Role of TNIK in Sepsis-Induced Cardiomyopathy
Wenwen Yang1, Aizhen Zhao1, Wangrui Lei1
1Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China.
Abstract:
Heart failure induced by sepsis is considered one of the foremost contributors to mortality in intensive care unit (ICU) patients. However, the molecular mechanism of myocardial damage in sepsis has not been fully elucidated at present. TNF receptor-associated factor-2 and Nck-interacting protein kinase (TNIK) are members of the germinal center kinase superfamily. TNIK exhibits a pivotal role as a conserved modulator of glucose and lipid homeostasis. Here, we aimed to investigate the potential direct roles of TNIK and whether TNIK exerts anti-septic myocardial damage by regulating the NLRP3 pathway. We initially revealed that TNIK was the crucial involvement of septic myocardial injury. Subsequently, we constructed a cecal ligation and puncture (CLP) mouse model and employed LPS-induced injury in HL-1 cardiomyocytes. Our observations revealed an upregulation of TNIK levels in both CLP-injured mice and LPS-treated HL-1 cells. However, TNIK inhibitor TNIK-IN-7 or siRNA attenuated cardiomyocyte LPS injury. Especially, TNIK siRNA can significantly downregulate TNIK as well as decrease NLRP3 and IL-1β mRNA and protein levels, though the explicit molecular mechanisms of TNIK-NLRP3 in septic myocardial require further investigation. Together, our investigation presents novel evidence suggesting TNIK as a potential therapeutic target for the prevention and therapeutic intervention in sepsis-induced cardiomyopathy.
Insights
Sepsis-induced heart failure is a major ICU mortality cause. This study reveals Tumor Necrosis Factor Receptor-Associated Factor-2 and Nck-Interacting Protein Kinase (TNIK) as a key player in septic myocardial damage, suggesting it as a therapeutic target.
Area of Science:
- Molecular mechanisms of sepsis-induced myocardial damage.
- Cardiovascular research and critical care medicine.
Background:
- Sepsis-induced heart failure is a leading cause of mortality in intensive care units (ICUs).
- The precise molecular pathways underlying septic myocardial injury remain incompletely understood.
- Tumor Necrosis Factor Receptor-Associated Factor-2 and Nck-Interacting Protein Kinase (TNIK) is a conserved modulator of glucose and lipid homeostasis.
Purpose of the Study:
- To investigate the direct role of TNIK in sepsis-induced myocardial damage.
- To determine if TNIK regulates the NLRP3 inflammasome pathway in septic cardiomyopathy.
- To explore TNIK as a potential therapeutic target for sepsis-induced myocardial injury.
Main Methods:
- Construction of a cecal ligation and puncture (CLP) mouse model for sepsis.
- Utilizing lipopolysaccharide (LPS)-induced injury in HL-1 cardiomyocytes.
- Employing TNIK inhibitor (TNIK-IN-7) and small interfering RNA (siRNA) to assess TNIK's role.
- Measuring TNIK, NLRP3, and IL-1β mRNA and protein levels.
Main Results:
- TNIK levels were significantly upregulated in both CLP-induced septic mice and LPS-treated cardiomyocytes.
- Inhibition or knockdown of TNIK attenuated LPS-induced cardiomyocyte injury.
- TNIK knockdown notably decreased the expression of NLRP3 and IL-1β at both mRNA and protein levels.
- TNIK was identified as crucial in septic myocardial injury.
Conclusions:
- TNIK plays a significant role in the pathogenesis of sepsis-induced myocardial damage.
- TNIK inhibition or knockdown mitigates cardiac injury in a sepsis model.
- TNIK may exert its protective effects by modulating the NLRP3 inflammasome pathway.
- TNIK represents a promising therapeutic target for sepsis-induced cardiomyopathy.
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