© 2000 American Heart Association, Inc.
Vascular Biology |
Lipoteichoic Acid Induces Delayed Protection in the Rat Heart
A Comparison With Endotoxin
From The William Harvey Research Institute, St. Bartholomew’s and The Royal London School of Medicine and Dentistry (K.Z., P.K.C., C.T.), London, UK; the Department of Pharmacology (S.F., J.P.), University of Frankfurt, Frankfurt, Germany; the Department of Pathology (M.O.) and the Department of Clinical Chemistry (G.H.), University of Mainz, Mainz, Germany; and the Department of Pharmacology (S.C.), University of Messina, Messina, Italy.
Correspondence to Dr Kai Zacharowski, The William Harvey Research Institute, Charterhouse Square, London EC1 M 6BQ, UK. E-mail k.zacharowski{at}mds.qmw.ac.uk
Abstract—Classic ischemic
preconditioning transiently (30 to 120 minutes) protects the
myocardium against subsequent lethal
ischemia/reperfusion injury. After dissipation of this acute
protection, a second window of protection (SWOP) appears 12 to 24 hours
later; this SWOP lasts up to 3 days. Several triggers induce a SWOP,
including brief repetitive cycles of coronary artery occlusion,
rapid ventricular pacing, stimulation of adenosine
A1 receptors, and administration of wall fragments of
Gram-negative bacteria, such as lipopolysaccharide (LPS). The
aim of this study was to investigate whether lipoteichoic acid (LTA), a
cell wall fragment of Gram-positive bacteria, can induce a SWOP in a
rat model of left anterior descending coronary artery (LAD)
occlusion (25 minutes) and reperfusion (2 hours). Thus, 166 male Wistar
rats were pretreated (2 to 24 hours) with saline, LTA (1 mg/kg IP), or
LPS (1 mg/kg IP) and subjected to LAD occlusion/reperfusion.
Pretreatment with LTA or LPS for 16 hours led to a substantial,
65%, reduction in infarct size and a reduction in the release of
cardiac troponin T into the plasma. The dose of LTA used had no toxic
effect (on any of the parameters studied), whereas the same
dose of LPS caused a time-dependent activation of the coagulation
system and liver injury. By use of RNase protection assays, it was
determined that LPS caused a time-dependent induction of tumor necrosis
factor-
, interleukin-1ß, and manganese superoxide dismutase mRNA
content in the heart, whereas LTA failed to induce manganese superoxide
dismutase. LPS also caused an upregulation of the expression of
intercellular adhesion molecule-1 and P-selectin, whereas LTA
downregulated these molecules and attenuated the accumulation of
polymorphonuclear granulocytes caused by myocardial
ischemia/reperfusion. This study demonstrates for the first
time that pretreatment with LTA at 8 to 24 hours before myocardial
ischemia significantly reduces (1) infarct size, (2) cardiac
troponin T, and (3) the histological signs of tissue
injury in rats subjected to LAD occlusion and reperfusion. The
mechanism(s) underlying the observed cardioprotective effects of LTA
warrants further investigation but is likely to be related to its
ability to inhibit the interactions between the coronary
vascular endothelium and polymorphonuclear
granulocytes. Therefore, LTA represents a novel and promising
agent capable of enhancing myocardial tolerance to
ischemia/reperfusion injury.
Key Words: lipopolysaccharide • lipoteichoic acid • myocardial infarct size • delayed preconditioning • myocardial ischemia
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