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.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver, USA.
Meng
X
X
Shames
B D
BD
Pomerantz
B
B
Donnahoo
K K
KK
Banerjee
A
A
Harken
A H
AH
D000818:Animals; D004337:Drug Carriers; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000008:administration & dosage* / Q000096:biosynthesis; D006358:Hot Temperature; D008070:Lipopolysaccharides / Q000633:toxicity*; D008081:Liposomes; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004337:Drug Carriers; D018840:HSP70 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; D008081:Liposomes