Role of Toll-like Receptors in the Mechanism(s) of Bacterial Lipid-Induced Cardioprotection and Experimental Heart Failure

• Applicant: Professor Kai Zacharowski, Ph.D.
• Subject Area: Anaesthesiology
• Term: from 2004 to 2007
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5425842

Cardiovascular disease occurs in up to 20 million people in Germany. We have discovered that lipopolysaccharide (LPS), lipoteichoic acid (LTA) and peptidoglycan (PepG) (lipids derived from the cell wall of bacteria) reduce cellular damage following myocardial infarction. These bacterial lipids can activate toll-like receptors (TLRs), which have been identified as essential elements of an immune response. Our data show that (i) low dose LPS, LTA or PepG are cardioprotective, (ii) bacterial lipids activate NFkB and induce cytokine production in the heart, (iii) antibodies directed against tumour necrosis factor or interleukin-1 do not abolish the cardioprotective effects of LPS or LTA, and (iv) LPS and LTA have contrary and similar effects on the coronary vascular endothelium-neutrophil system. The project is designed to investigate whether bacterial lipid-induced cardioprotection is mediated via TLRs using molecular, genetic and pharmacological methods. In a first step, TLR2, TLR4 and TLR2/4-knockout mice will be treated with bacterial lipids and subjected to myocardial infarction. In case of TLR-mediated cardioprotection, we wish to characterise the up-and downstream signalling pathways involved. We then investigate the activation of the coronary vascular endotheliumneutrophil system. Finally, we intend to correlate the activation of TLRs with the degree of heart failure occurring in our model. This project aims to increase our knowledge for the prevention and treatment of cardiovascular disease.

• DFG Programme: Research Grants