Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Kumar, Aseem; Kumar, Anand; Paul, M.; Brabant, Danielle; Parissenti, Amadeo M.; Ramana, Chilakamarti V.; Xu, Xiulong; Parrillo, Joseph E.

doi:10.1074/jbc.m508416200

Cited by 59 publications

(39 citation statements)

References 74 publications

(78 reference statements)

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“…Septic plasma can be viewed as a pool of cytokines, chemokines, and other inflammatory mediators that have the potential to activate several intracellular signaling pathways in cardiac myocytes, some of which may lead to conversion of the cardiac myocytes to a proinflammatory phenotype (17). Previous studies (17,22,27) indicate that septic plasma can convert adult human and rat cardiomyocytes, as well as mouse neonatal myocytes, to a proinflammatory phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Important role of p38 MAP kinase/NF-κB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype

Yang¹,

Wu²,

Martin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Septic plasma can convert murine cardiac myocytes to a proinflammatory phenotype. These myocytes 1) have increased nuclear levels of nuclear factor-B (NF-B), 2) release CXC chemokines, and 3) promote polymorphonuclear neutrophil (PMN) transendothelial migration. The purpose of the present study was to evaluate the role of the mitogen-activated protein (MAP) kinases [p38 MAP kinase, extracellular signal-regulated kinase (ERK) 1/2, and c-Jun NH 2-terminal kinase (JNK)] as upstream intracellular signaling components involved in this phenomenon. Feces-induced peritonitis (FIP) was employed as a model of sepsis. In vitro, cardiac myocytes were treated with plasma (20%) obtained 6 h after either sham (saline) or FIP procedures. Myocyte supernatants were used for 1) detection of the CXC chemokines (enzyme-linked immunosorbent assay) and 2) assessment of their ability to promote PMN transendothelial migration. In vivo, myocardial PMN accumulation was assessed by measuring myeloperoxidase (MPO) activity and function (dF/dt and heart work). Treatment of cardiac myocytes with septic plasma activated p38 MAP kinase and ERK1/2, but not JNK. Blockade approaches (inhibitors or small-interference RNA) indicated that only p38 MAP kinase played a role in the conversion of the myocytes to a proinflammatory phenotype. Time course studies indicated that phosphorylation of p38 MAP kinase preceded the phosphorylation of NF-B p65. Inhibition of p38 MAP kinase (SB-202190) blocked both NF-B p65 phosphorylation and NF-B nuclear translocation. Confirmatory studies in vivo indicated that FIP resulted in an increase in myocardial MPO activity and dysfunction, events reversed by the inhibitor of p38 MAP kinase. Collectively, these data indicate that the cardiomyocyte p38 MAP kinase/NF-B signaling pathway plays an important role in the sepsis-induced conversion of myocytes to a proinflammatory phenotype.

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Section: Discussionmentioning

confidence: 99%

“…Previous studies (17,22,27) indicate that septic plasma can convert adult human and rat cardiomyocytes, as well as mouse neonatal myocytes, to a proinflammatory phenotype. The three MAP kinases (ERK1/2, JNKs, and p38 MAP kinase) can be both activated by inflammatory mediators and, in turn, generate inflammatory mediators (12,31,40,47).…”

Section: Discussionmentioning

confidence: 99%

Important role of p38 MAP kinase/NF-κB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype

Yang¹,

Wu²,

Martin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Aside from these cellular measurements of apoptosis, the ability of septic or severely injured patients' serum to induce apoptosis has been largely described on various cell culture populations (151)(152)(153). Accordingly, several groups observed increased serum levels of proapoptotic factors such as sFas or sFasL in septic and critically ill patients (17,154,155).…”

Section: Monitoring Of Apoptosismentioning

confidence: 99%

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Monneret

Venet

Pachot

et al. 2008

Mol Med

306

323

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“…Activation of various caspases, the effectors of apoptosis, and mitochondrial cytochrome c release have been reported in cardiomyocytes following septic challenge (139)(140)(141). Caspase 3 activation via endotoxin might also be associated with altered calcium myofilament responses, cleavage of contractile proteins, and sarcomere disorganization (142).…”

Section: Apoptosismentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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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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Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-κB and Induces Apoptosis in Human Cardiac Myocytes

Cited by 59 publications

References 74 publications

Important role of p38 MAP kinase/NF-κB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype

Important role of p38 MAP kinase/NF-κB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Molecular Events in the Cardiomyopathy of Sepsis

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