Endotoxin-Induced Myocardial Dysfunction

Abstract

Abstract-The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin. Key Words: sepsis Ⅲ myocardial dysfunction Ⅲ migration inhibitory factor neutralization Ⅲ lipopolysaccharides S evere sepsis and septic shock are leading and growing causes of morbidity and mortality in hospitalized patients, 1 and contribute to an incidence of almost 250 cases per 100 000 population per year in the United States. 2 These conditions account for the deaths of 150 000 Americans per year, and more than 75% involve cardiovascular failure with severe, sustained, and sometimes refractory hypotension. 1-2 Over the last decade, it has become clear that myocardial dysfunction is linked to cardiovascular failure in human and experimental septic shock. 3-7 Bacteria or endotoxins (lipopolysaccharides [LPS]) contribute to and initiate a sequence of cellular events that lead to decreased contractile efficiency and left ventricular enlargement and dysfunction. 8 -10 The sequelae of systemic infection can produce reversible or irreversible damage to cardiomyocytes, such as impairment of intracellular calcium homeostasis, alterations of excitation/contraction coupling, and enhanced programmed cell death (or apoptosis). 10 -12 Apoptosis is a new culprit for cardiac failure and sepsis-induced heart dysf...

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

“…This is in agreement with already published data indicating significant inhibition of pro-apoptotic potential (BAX/Bcl-2 ratio) after MIF protein inhibition in cardiomyocytes observed both in vivo and in vitro. 26,28 Interestingly, although ISO-1 demonstrated protective effect on pancreatic islets, it upregulated caspase 3 and BIM expressions. This could be only a transient increase detected after 6 h Figure 5 For caption see page 693.…”

“…[31][32][33] However, MIF acts as a pro-apoptotic molecule as well through engaging mitochondriarelated apoptotic pathway. [25][26][27][28] The initial step in the apoptosis induction is assembling of BAX molecules into large homo-oligomers that damage the outer mitochondrial membrane, consequently becoming permeable to proteins normally constrained within the intermembrane space of the mitochondria. On the other hand, presence of Bcl-2 proteins confronts membrane pore formation.…”

“…23 There is also evidence that MIF promotes apoptotic cell death in primary bladder muscle cells, B lymphocytes, tumor cell lines, cardiomyocytes and neurons. [24][25][26][27] The mechanism of apoptosis induction by MIF is not well understood. There is some circumstantial evidence that suggests the involvement of mitochondrial dysfunction in MIF-mediated apoptosis.…”

“…There is some circumstantial evidence that suggests the involvement of mitochondrial dysfunction in MIF-mediated apoptosis. 26 Additionally, MIF activates caspase 3, BAX and MAPK, all of which may be involved in apoptosis induction in different cell types and different settings. 28,29 As MIF is implicated in diabetes pathogenesis, this study explored its local and systemic production and expression during high-fat diet (HFD)-induced T2D in C57BL/6 mice.…”

A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis

“…To test this, we examined the effect of MIF/TTX DNA vaccination on the mRNA levels of inflammatory cytokines in the lung tissues of mice with sepsis. As neutralization of MIF was reported to be associated with decreased mRNA expressions of IL-1b and IL-6 in LPS-induced rat myocardial dysfunction model, 25 mRNA levels of these proinflammatory cytokines were also measured. We found that MIF/TTX DNA vaccination suppressed TNF, IL-1b and IL-6 expression in the lung upon challenge with LPS or CLP.…”