Enhanced monocyte chemoattractant protein-1 production in aging mice exaggerates cardiac depression during endotoxemia

Abstract

IntroductionEndotoxemia and the systemic inflammatory response syndrome have a significant impact on post-surgery outcome, particularly in the elderly. The cytokine response to endotoxin is altered by aging. We tested the hypothesis that vulnerability to endotoxemic cardiac depression increases with aging due to age-related augmentation of myocardial inflammatory responses.MethodsAdult (4 to 6 months) and old (20 to 22 months) C57/BL6 mice were treated with endotoxin (0.5 mg/kg, iv). Left ventricle (LV) function was assessed using a microcatheter system. Chemokines and cytokines in plasma and myocardium were analyzed by enzyme-linked immunosorbent assay (ELISA). Mononuclear cells in the myocardium were examined using immunofluorescence staining.ResultsOld mice displayed worse LV function (cardiac output: 3.0 ± 0.2 mL/min versus 4.4 ± 0.3 mL/min in adult mice) following endotoxin treatment. The exaggerated cardiac depression in old mice was associated with higher levels of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC) in plasma and myocardium, greater myocardial accumulation of mononuclear cells, and greater levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) in plasma and myocardium. Neutralization of MCP-1 resulted in greater reductions in myocardial mononuclear cell accumulation and cytokine production, and greater improvement in LV function in old mice while neutralization of KC had a minimal effect on LV function.ConclusionOld mice have enhanced inflammatory responses to endotoxemia that lead to exaggerated cardiac functional depression. MCP-1 promotes myocardial mononuclear cell accumulation and cardiodepressant cytokines production, and plays an important role in the endotoxemic cardiomyopathy in old mice. The findings suggest that special attention is needed to protect the heart in the elderly with endotoxemia.

Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice

“…As enhanced MCP-1 production and mononuclear cell accumulation in the myocardium play important roles in the exaggerated cardiac dysfunction in old endotoxemic mice [4], we compared MCP-1 levels and myocardial mononuclear cell density in old WT mice and old IL-37tg mice. As shown in Figure 3A, MCP-1 levels in plasma and myocardial tissue after LPS treatment were significantly lower in old IL-37tg mice in comparison to old WT mice (420±32 pg/ml vs. 1318 pg/ml±128 pg/ml and 310±23 pg/mg vs. 692±56 pg/mg, both P <0.05).…”

“…Excessive production of pro-inflammatory mediators caused by bacterial lipopolysaccharide (LPS) frequently leads to cardiac dysfunction. We and others have observed that LPS induces cardiac contractile depression through up-regulation of myocardial production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 [2–4]. Importantly, morbidity and mortality due to the systemic inflammatory response syndrome associated with trauma or sepsis are significantly increased in the elderly [5, 6].…”

“…Old animals are found to display enhanced systemic and myocardial inflammatory responses to LPS [4, 7]. We previously reported that enhanced monocyte chemoattractant protein-1 (MCP-1) production in old endotoxemic mice has a critical role in mononuclear cell accumulation and cytokine production in the myocardium and contributes to the mechanism of exaggerated cardiac contractile depression.…”

Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1

“…One of the inflammatory molecules that plays a role in the human ovulatory process and relates to both aging and obesity [14][15][16][17][18][19] is monocyte chemoattractant protein-1 (MCP-1) [20]. MCP-1, a polypeptide composed of 76 amino acids, is produced by various cell types including endothelial cells, fibroblasts, tumor cells, monocytes, and macrophages [20,21].…”

“…In humans, physiologic levels of MCP-1 are important for the ovulatory process [20]. As far as aging and obesity, data have shown that systemic MCP-1 levels are increased in aging animals [14][15][16] and that there is an increased abundance of this pro-inflammatory chemokine in both white adipose tissue and plasma in obese animals [17][18][19]. Additionally, we have recently demonstrated in women undergoing in vitro fertilization (IVF) that serum and follicular fluid MCP-1 are positively correlated with body mass index (BMI) (Obehi et al, manuscript under review).…”