LPS-mediated inflammation in cardiovascular diseases

Abstract

Emergence and development of heart failure as a manifestation of atherosclerotic process or primary lesion to cardiomyocytes in cardiomyopathies can be caused by blood accumulation of endotoxins, components of bacterial cells, such as lipopolysaccharide (LPS) of gram-negative bacterial cell wall. LPS binding to TOLL-like receptors (TLR) triggers signaling pathways to induce synthesis of pro-inflammatory cytokines, production of reactive oxygen and nitrogen species, and development of oxidative stress and inflammation at the site of atherosclerotic lesion. Activation of LPS-TLR4-signaling pathways in platelets contributes to development of thrombosis. An imbalance between oxidative stress and antioxidant mechanisms is observed in myocardial ischemia and heart failure. The myocardium has endogenous restorative mechanisms, including the systems of thioredoxin (Trx) and glutathione (GSH) designed for removing active oxygen species and reducing oxidized proteins, some of which are involved in LPS-TLR4 signaling pathways. For example, GSH is able to modify the adaptor protein MyD88 while
Trx is a direct inhibitor of protein kinase ASK1, to facilitate suppression of proapoptotic signaling pathways during acute inflammation in cardiomyocytes. In addition, Trx prevents mitochondrial dysfunction, increases ATP production, inhibits apoptosis and, thereby, exerts a cardioprotective effect.