Inhibition of Mitochondrial Permeability Transition Prevents Sepsis-Induced Myocardial Dysfunction and Mortality

Larché, Jérôme; Lancel, Steve; Hassoun, Sidi Mohamed; Favory, Raphaël; Decoster, Brigitte; Marchetti, Philippe; Chopin, C.; Nevière, Rémi

doi:10.1016/j.jacc.2006.02.069

Cited by 153 publications

(119 citation statements)

References 29 publications

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“…Mitochondrial dysfunction may contribute to decreased cardiac contractility. The beneficial effect of cyclosporin A in our experiments confirms that mPTP opening contributes to mitochondrial dysfunction during sepsis (39). Opening of the mPTP can be triggered by calcium overload (24).…”

Section: Discussionsupporting

confidence: 78%

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

et al. 2017

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Section: Discussionsupporting

confidence: 78%

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

et al. 2017

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“…Letztere Theorie vermutet, dass die sepsisassoziierte myokardiale Dysfunktion eine protektive Adaptation an den reduzierten myokardialen Energiestatus wäh-rend der septischen Kardiomyopathie darstellt, der aus der mitochondrialen Dysfunktion resultiert (vergleichbar zu der Hibernation während der myokardialen Ischämie; [15] Zu den Veränderungen der Mitochondrien während der septischen Kardiomyopathie zählen ultrastrukturelle Schäden, die zur Freisetzung mitochondrialer DNA [97] und zur Zunahme der mitochondrialen "permeability transition pore" führen [58]. Die pharmakologische Inhibition der mitochondrialen "permeability transition pore" mittels Ciclosporinderviaten kann die kardiale Funktion verbessern und die Sterblichkeit im Mausmodell der polymikrobiellen Sepsis reduzieren [58]. [113].…”

Section: Mitochondrien Und Energiehaushaltunclassified

Herz in der Sepsis

et al. 2017

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“…Interestingly, mitochondrial DNA seems to be more receptive to LPS-induced damage than nuclear DNA (124,134). Finally, the mitochondrial permeability transition pore seems to be involved in sepsis-induced mitochondrial damage in the myocardium, because its inhibition significantly improved cardiac function and reduced mortality in rodents (135).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

“…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

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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Inhibition of Mitochondrial Permeability Transition Prevents Sepsis-Induced Myocardial Dysfunction and Mortality

Cited by 153 publications

References 29 publications

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

Herz in der Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

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