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 whether functional heat-shock protein 72 (HSP-72) may be delivered into the heart, (2) determine whether HSP-72 itself is protective against endotoxin (lipopolysaccharide [LPS]-induced cardiodepression, and (3) compare relative protection and time courses required for protection for thermally induced HSP-72 versus liposomally introduced HSP-72. METHODS: HSP-72 was introduced (liposomal HSP-72) or induced (heat shock, 42 degrees C x 15 minutes, 24 hours before) in rat heart before LPS administration (0.5 mg/kg intraperitoneal or ex vivo coronary infusion). Western blot 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 functioning HSP-72 into the myocardium. LPS induced cardiodepression; however, heat shock pretreatment abolished LPS-induced contractile dysfunction. A direct connection was found between HSP-72 and protection derived from liposomal transfer experiments that similarly reduced LPS-induced cardiodepression. CONCLUSIONS: (1) HSP-72 prevents LPS-induced myocardial contractile dysfunction, (2) liposomal transfer of HSP-72 into the myocardium provides the first direct mechanistic connection between myocardial HSP-72 and protection against LPS, (3) HSP-72 induction requires 24 hours and liposomal transfer of HSP-72 requires 90 minutes, and (4) HSP-72 may offer a clinically acceptable means of protecting the heart.