Nitric oxide-dependent mechanism of anti-ischemic myocardial protection induced by monophosphoryl lipid A

Monophosphoryl Lipid A (MLA) is a detoxified derivative of endotoxin and wa s first derived and purified from bacterial Lipopolysaccharide in 1980s. Th is pharmacological agent has been studied as a vaccine adjunct, anti-septic , or anti-tumor agent by means of its immunomodulatory properties. In addit ion, MLA is one of the most well documented protective drugs against cardia c ischemia/reperfusion injury in various animal species. Mechanisms involve d with the MLA-induced cardioprotection are still not fully understood. A k ey role for ATP-sensitive potassium channels and inducible nitric oxide syn thase (iNOS) has been proposed. This article provides a brief overview on t he updated understanding of MLA-induced cardioprotection and focuses on the new evidence and insights that were brought into the field by a number of new publications during 1998 - 1999. Our recent study in a globally ischemi c mouse heart model is particularly highlighted. An obligatory role for nit ric oxide (NO) in mediating the delayed cardioprotective effect induced by MLA via induction of iNOS was double-confirmed by using S-methylisothiourea (SMT) - a specific inhibitors of iNOS as well as the iNOS gene knockout mi ce. A direct association of the MLA-induced infarct size reduction with inc reased NO production was also demonstrated in this study. Future studies sh ould target on identifying the key type(s) of cytokine and the receptors as well as free radical-activated transcription factors that may be responsib le for induction of iNOS and the subsequent anti-ischemic cardioprotection with MLA. Information gathered in the studies on MLA may eventually enhance our understanding in the mechanisms of delayed phase of myocardial precond itioning and its clinical applications.