MONOPHOSPHORYL LIPID-A INDUCES PHARMACOLOGICAL PRECONDITIONING IN RABBIT HEARTS WITHOUT CONCOMITANT EXPRESSION OF 70-KDA HEAT-SHOCK PROTEIN

The purpose of this study was to evaluate the protective effect of a n ew endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three gr oups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion, First group of rabbits (n = 6) were treated with 0.35 mi vehicle (40 % propylene glycol, 10 % ethanol in w ater). The second and third group of rabbits (n = 6-8) were treated wi th MLA (35 mu g/kg, i.v.) 12 and 24 hours prior to ischemia and reperf usion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion d emonstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/- 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8.6%, mean +/- S.E.M, p < 0.05), No significant differences in the in farct size was observed between the 12 and 24 h MLA treated groups. Th e area at risk was not significantly different between the three group s. Baseline values of heart rate, systolic and diastolic blood pressur e were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure dur ing reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/gro up) demonstrated no increase in the expression of the inducible form o f HSP 70 following treatment with MLA. We conclude that MLA has signif icant anti-infarct effect in rabbit which is not mediated by the cardi oprotective protein HSP 70. The anti-infarct effect of this drug is su perior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic precondi tioning afforded by MLA is accomplished via a unique pathway that bypa sses the usual intracellular signaling pathways which lead to the myoc ardial protection with the expression of heat shock proteins.