Lipoteichoic Acid Induces Delayed Protection in the Rat Heart

Abstract

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 A 1 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, Ϸ65%, 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-1␤, 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 Ⅲ lipoteichoic acid Ⅲ myocardial infarct size Ⅲ delayed preconditioning Ⅲ myocardial ischemia D uring coronary artery angioplasty or open heart surgery, regional or global iatrogenic cardiac ischemia is a common event. Reperfusion of previously ischemic myocardium leads to ischemia/reperfusion injury with enhanced propagation of arrhythmias, 1 stunning, 2 and cardiomyocyte cell death. 3 Over the last few years, the population of patients with coronary artery disease undergoing coronary artery angioplasty or bypass surgery has increased, as h...

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

“…For example, hearts isolated from rats pretreated with a low dose of LPS (0.5 mg/kg) 24 h before had a better preserved myocardial function after I/R compared with the saline-treated control hearts (18,105). Similar cardiac protection in LPS-treated animals was observed in vivo and in different animal models of I/R injury, such as rabbit (13,99), rat (18,88,106,138,155,166,167), and mice (48). The cardioprotective effect of LPS usually occurs between 12-24 h after the administration of LPS and is abolished by cycloheximide (106), suggesting a mechanism involving the de novo synthesis of cardioprotective proteins.…”

“…In animal models of I/R injury (13,18,48,88,89,99,106,138,155,166,167), in both in vivo (13,48,99,138,155,166,167) and ex vivo (18,88,106), a prior systemic administration of a sublethal dose of LPS reduces subsequent MI and improved cardiac functions. For example, hearts isolated from rats pretreated with a low dose of LPS (0.5 mg/kg) 24 h before had a better preserved myocardial function after I/R compared with the saline-treated control hearts (18,105).…”

“…In animal models of ischemic cardiac injury, the role of TLRs is incompletely defined. For example, the systemic administration of a sublethal dose of LPS, which signals through TLR4, reduced the subsequent ischemic MI and improved cardiac functions both in vivo and in isolated hearts (13,18,89,99,106,138,155,166,167). The activation of TLR4-myeloid differentiation primary-response gene 88 (MyD88) signaling also protects cardiomyocytes against apoptosis (26,170).…”

Lipopolysaccharide pretreatment protects against ischemia/reperfusion injury via increase of HSP70 and inhibition of NF-κB

“…Ischemic preconditioning is a well-described cardioprotective strategy in which brief exposure to ischemia remarkably enhances the ability of heart to withstand a subsequent ischemia/reperfusion injury Churchill et al 2010). Numerous studies also have shown that gram-negative bacterial LPS induced myocardial protection (Zacharowski et al 2000;Meng et al 1997). Specifically, pretreatment of rats with LPS for 24 h increases myocardial functional recovery in Fig.…”

Mechanisms of Cardiac Depression Caused by Lipoteichoic Acids From Staphylococcus aureus in Isolated Rat Hearts

“…27,28 In the myocardium of either S aureus-or LTA-treated rats, both TNF-␣ and IL-1␤ mRNA were found to be upregulated. 21,29 Like LPS, LTA has been shown to bind to CD14 and Toll-like receptors (TLRs) to induce activation of nuclear factor-B (NF-B), 30 -32 and cardiac expression of TLR2 was the prerequisite for cardiac depression associated with myocardial NF-B activation and TNF-␣ and IL-1␤ synthesis. 21 This may represent the prerequisite for the observation that LTA stimulates cytokine production and NO release in different cell types.…”