Liposomal delivery of heat-shock protein 72 into the heart prevents endotoxin-induced myocardial contractile dysfunction

Background, The purposes of this study were to (1) determine whetherfunctio nal heat-shock protein 72 (HSP-72) may be delivered into the heart, (2) det ermine whether HSP-72 itself is protective against endotoxin (lipopolysacch aride [LPS])-induced cardiodepression, and (3) compare relative protection and time courses required for protection for thermally induced HSP-72 versu s liposomally introduced HSP-72. Methods, HSP-72 was introduced (liposomal HSP-72) or induced (heat shock; 4 2 degrees C x I? minutes, 24 hours before) in rat heart before LPS administ ration (0.5 mg/kg intraperitoneal or ex vivo coronary infusion). Western bl ot analysis for HSP-72 was used to confirm its expression. Left ventricular developed pressure (Langendorff) was used as an index of cardiac function. Results, Direct intracoronary perfusion of liposomal HSP-72 delivered funct ioning HSP- 72 into the myocardium. LPS induced cardiodepression; however; heat shock pretreatment abolished LPS-induced contractile dysfunction. A di rect connection was found between HSP-72 and protection derived from liposo mal transfer experiments that similarly reduced LPS-induced cardiodepressio n. Conclusions. (I) HSP-72 prevents LPS-induced myocardial contractile dysfunc tion, (2) liposomal transfer of HSP-72 into the myocardium provides the fir st direct mechanistic connection between myocardial HSP-72 and protection a gainst LPS, (3) HSP-72 induction requires 24 hours and lioosomal transfer o f HSP-72 requires 90 minutes, and (4) HSP-72 may offer a clinically accepta ble means of protecting the heart.