Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts.

Abstract

Hearts isolated from rats pretreated 24 hr before with endotoxin had increased myocardial catalase activity, but the same superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities, as hearts from untreated rats. Hearts isolated from rats pretreated with endotoxin 24 hr before also had increased myocardial function (decreased injury) after ischemia and reperfusion (Langendorff apparatus, 3rC), as assessed by measurement of ventricular developed pressure, contractility (+dP/dt), and relaxation rate (-dP/dt), compared to control hearts. In contrast, hearts isolated from rats pretreated with endotoxin 1 hr before isolation or hearts perfused with endotoxin did not have increased catalase activity or decreased injury following ischemia and reperfusion. Aminotriazole pretreatment prevented increases in myocardial catalase activity and myocardial function after ischemiareperfusion in hearts from endotoxin-pretreated rats. The results suggest that endotoxin pretreatment decreases cardiac ischemia-reperfusion injury and that increases in endogenous myocardial catalase activity contribute to protection.Hydrogen peroxide generated by xanthine oxidase appears to contribute to reperfusion injury of isolated ischemic rat hearts (1-4). This impression is based on observations that inhibition of xanthine oxidase or scavenging of H202 by addition of exogenous 02-metabolite scavengers decreases reperfusion injury of isolated ischemic hearts (1-4). Because endotoxin pretreatment increases endogenous lung antioxidant activities and decreases lung injury from hyperoxia (5), we hypothesized that endotoxin pretreatment would also increase endogenous myocardial antioxidant activities and, as a result, decrease myocardial susceptibility to ischemiareperfusion injury. Using a standard Langendorff isolated "blood-free" perfused rat heart model, we found that hearts from endotoxin-pretreated rats had increased catalase activity and decreased susceptibility to ischemia-reperfusion injury. MATERIALS AND METHODSPretreatment with Endotoxin and/or Aminotriazole. Quarantined male Sprague-Dawley rats (300-325 g) were treated with saline (0.9% NaCI) or endotoxin (500 ,ug/kg of body weight, i.p., Salmonella typhimurium phenol extract, Sigma) in 5 mM potassium phosphate buffer (pH 7.4) 24 hr or 1 hr before heart isolation. Some rats were pretreated with endotoxin 24 hr before and low-dose aminotriazole (50 mg/kg, i.p. in potassium phosphate buffer, Sigma) 12 hr before or with high-dose aminotriazole (500 mg/kg, i.p. in potassium phosphate buffer) alone 12 hr before isolation.Assay (7), and glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase (8) activities. Preparation of Isolated Rat Hearts. Rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and heparinized (500 units, via the right atrium). Hearts were rapidly excised and then perfused (70 mmHg; 1 mmHg = 133 pascals) in retrograde fashion at the aortic root with a Krebs-Henseleit so...

Lipopolysaccharide Improves Cardiomyocyte Survival and Function after Serum Deprivation

“…Although LPS is well known for its roles in systemic inflammation and myocardial depression in bacterial sepsis, evidence from several lines of investigation suggests that systemic administration of sublethal doses of LPS protect the myocardium against subsequent ischemia and reperfusion injury (23)(24)(25)(26)(27). However, the mechanisms leading to the LPS cardio-protective effect is unknown.…”

“…Intriguingly, evidence from several lines of investigation suggests that LPS may activate intracellular survival mechanisms and protect the myocardium against ischemia and reperfusion injury. For example, in animal models, administration of LPS or its nonpyrogenic derivative mono-phosphoryl lipid A reduces cardiac arrhythmia and myocardial infarction after ischemia and reperfusion injury (IRI) (23)(24)(25)(26)(27). In a rabbit model systemic administration of LPS before ischemia led to a reduction in infarct size by 54% (28).…”

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). 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).…”

“…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).…”