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Published on: May 2, 2018
Cathelicidin deficiency exacerbates cardiac dysfunction in lipopolysaccharide-induced endotoxaemic mice
Tingting Zhai1,2, Jie Zhang1,2, Yacheng Zhang1,2
1Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Insights
Antimicrobial peptide cathelicidin (Camp) protects the heart during sepsis by reducing inflammation. Camp deficiency worsens septic cardiomyopathy, while its administration lowers mortality and inhibits TNF-α production.
Area of Science:
- Cardiovascular Research
- Infectious Diseases
- Immunology
Background:
- Sepsis-induced cardiomyopathy is a severe complication with limited treatment options.
- The role of cathelicidin (Camp), an antimicrobial peptide, in septic cardiomyopathy remains unclear.
- Camp is known for its antimicrobial and immunomodulatory functions.
Purpose of the Study:
- To investigate the role of cardiac cathelicidin in lipopolysaccharide (LPS)-induced endotoxemia and septic cardiomyopathy.
- To determine the effect of Camp deficiency and administration on myocardial function and survival during sepsis.
- To elucidate the underlying mechanisms of Camp's protective effects in the heart.
Main Methods:
- Lipopolysaccharide (LPS)-induced endotoxemia model in C57BL/6J wild-type (WT) and Camp knockout mice.
- D-galactosamine hydrochloride (D-GalN)-sensitized endotoxin shock model for mortality studies.
- Measurement of cardiac and circulating cathelicidin, and tumor necrosis factor-alpha (TNF-α) levels.
- In vitro studies using cultured neonatal mouse cardiomyocytes.
Main Results:
- LPS challenge induced cardiac and circulating cathelicidin expression, primarily from neutrophils and monocytes/macrophages.
- Camp deficiency exacerbated LPS-induced myocardial depression and increased TNF-α levels.
- CRAMP administration reduced mortality in endotoxin shock and inhibited LPS-induced TNF-α production in vivo and in vitro.
- CRAMP's inhibitory effect on TNF-α appears linked to LPS neutralization, not general TLR4 antagonism.
Conclusions:
- LPS-induced cathelicidin plays a protective role in the heart during sepsis.
- Cathelicidin mitigates septic cardiomyopathy, partly by inhibiting TNF-α production through LPS neutralization.
- Targeting cathelicidin may offer a therapeutic strategy for sepsis-induced cardiac dysfunction.
Abstract:
The therapeutic potential of the antimicrobial peptide cathelicidin (Camp) administration in sepsis has been widely investigated. However, little is known about the pathophysiological roles of cathelicidin in septic cardiomyopathy. In a lipopolysaccharide (LPS)-induced endotoxaemic model, we found that the mRNA and protein expression of cardiac cathelicidin were induced in C57BL/6J wild-type (WT) mice upon LPS challenge, accompanied by increased circulating cathelicidin levels. We showed that this peptide was mainly derived from neutrophils and monocytes/macrophages. Camp deficiency exacerbated LPS-induced myocardial depression, while the administration of CRAMP (the mature form of mouse cathelicidin) decreased the LPS-induced mortality in a D-galactosamine hydrochloride (D-GalN)-sensitized endotoxin shock model. In vivo, LPS-treated Camp knockout mice had a significant higher protein level of myocardial and circulating tumour necrosis factor-alpha (TNF-α), a major contributing factor to septic cardiomyopathy, compared to LPS-treated WT mice, while CRAMP administration inhibited LPS-induced TNF-α production in the heart and plasma in D-GalN-sensitized endotoxaemic mice. In vitro, CRAMP treatment suppressed LPS-induced Tnf-α mRNA expression in cultured neonatal mouse cardiomyocytes and reduced TNF-α secretion in the culture supernatant. The inhibitory effects of CRAMP on TNF-α production may be related to its neutralizing ability of LPS, since CRAMP application had no effects on another toll-like receptor 4 ligand paclitaxel-induced Tnf-α mRNA expression in cardiomyocytes. These findings suggest that LPS-induced cathelicidin protects the heart against myocardial depression partly through the inhibition of TNF-α production via neutralizing LPS.
