Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats*

Lancel, Steve; Pétillot, P; Favory, Raphaël; Stebach, Nicolas; Lahorte, Christophe; Danze, Pierre Marie; Vallet, B.; Marchetti, Philippe; Nevière, Rémi

doi:10.1097/01.ccm.0000156240.31913.4a

Cited by 29 publications

(23 citation statements)

References 26 publications

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“…Cardiac myocyte apoptosis plays a major role in cardiac dysfunction (24,25,41). Therefore, we examined the effect of GP administration on cardiac myocyte apoptosis in septic mice with the use of the TUNEL assay.…”

Section: Gp Inhibited Sepsis-induced Cardiac Myocyte Apoptosismentioning

confidence: 99%

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Ha¹,

Fang²,

Grant³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice. Am J Physiol Heart Circ Physiol 291: H1910 -H1918, 2006. First published June 9, 2006 doi:10.1152/ajpheart.01264.2005.-Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLPinduced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (P Ͻ 0.05) and cardiomyocyte apoptosis by 7.8-fold (P Ͻ 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% (P Ͻ 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3␤, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.

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Section: Gp Inhibited Sepsis-induced Cardiac Myocyte Apoptosismentioning

confidence: 99%

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Ha¹,

Fang²,

Grant³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Therefore, it is not surprising that anti-apoptotic strategies have reversed cardiac dysfunction (inhibition of caspases [particularly caspase 3] averted endotoxin-induced cardiac dysfunction and heart apoptosis) (137,143). Cyclosporin A, which inhibits mitochondrial permeability transition and cytochrome c release, or overexpression of anti-apoptotic Bcl-2 both prevented sepsis-induced myocardial dysfunction (135,144,145). Yet, there seem to be additional parameters involved in the caspase inhibitor-mediated cardioprotection, besides decreasing apoptotic cell death.…”

Section: Apoptosismentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

107

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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“…Cardiac myocyte apoptosis plays a major role in cardiac dysfunction following myocardial I/R injury (32)(33)(34). Activation of the PI3K/Akt signaling pathway decreases cardiac myocyte apoptosis following myocardial I/R (26 -29).…”

Section: Pi3k Inhibition With Wortmannin or Ly924002 Increased Cardiamentioning

confidence: 99%

Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism

Fang¹,

Ha²,

Ma³

et al. 2007

The Journal of Immunology

146

161

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TLRs play a critical role in the induction of innate and adaptive immunity. However, TLRs have also been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We have reported that TLR4−/− mice show decreased myocardial injury following I/R; however, the protective mechanisms have not been elucidated. We examined the role of the PI3K/Akt signaling pathway in TLR4−/− cardioprotection following I/R injury. TLR4−/− and age-matched wild-type (WT) mice were subjected to myocardial ischemia for 45 min, followed by reperfusion for 4 h. Pharmacologic inhibitors of PI3K (wortmannin or LY294002) were administered 1 h before myocardial I/R. Myocardial infarct size/area at risk was reduced by 51.2% in TLR4−/− vs WT mice. Cardiac myocyte apoptosis was also increased in WT vs TLR4−/− mice following I/R. Pharmacologic blockade of PI3K abrogated myocardial protection in TLR4−/− mice following I/R. Specifically, heart infarct size/area at risk was increased by 98% in wortmannin and 101% in LY294002-treated TLR4−/− mice, when compared with control TLR4−/− mice. These data indicate that protection against myocardial I/R injury in TLR4−/− mice is mediated through a PI3K/Akt-dependent mechanism. The mechanisms by which PI3K/Akt are increased in the TLR4−/− myocardium may involve increased phosphorylation/inactivation of myocardial phosphatase and tensin homolog deleted on chromosome 10 as well as increased phosphorylation/inactivation of myocardial glycogen synthase kinase-3β. These data implicate innate immune signaling pathways in the pathology of acute myocardial I/R injury. These data also suggest that modulation of TLR4/PI3K/Akt-dependent signaling pathways may be a viable strategy for reducing myocardial I/R injury.

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Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats*

Abstract: These observations suggest that both death receptor and caspase-mediated apoptosis processes are activated in this sepsis model. Bcl-2 overexpression before endotoxin challenge prevents myocardial dysfunction in rats and improves survival rate in mice.

Cited by 29 publications

References 26 publications

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice

Molecular Events in the Cardiomyopathy of Sepsis

Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism

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