Involvement of Mitochondrial Disorders in Septic Cardiomyopathy

Durand, Arthur; Duburcq, Thibault; Dekeyser, Thibault; Nevière, Rémi; Howsam, Michael; Favory, Raphaël; Preau, Sébastien

doi:10.1155/2017/4076348

Cited by 61 publications

(43 citation statements)

References 116 publications

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“…Evidence from our lab and others has demonstrated a major role for endotoxin lipopolysaccharides (LPS) released from Gram‐negative bacteria in the inflammatory response and cardiovascular homeostasis in sepsis (Pfalzgraff & Weindl, ; Ren et al, ; Zhang et al, ). Although antioxidants (such as metallothionein, insulin‐like growth factor I and catalase), mitochondrial protein aldehyde dehydrogenase (ALDH2) and ER chaperones have shown some promise in the treatment of septic cardiomyopathy (Ceylan‐Isik et al, ; Durand et al, ; Pang, Peng et al, ; Turdi et al, ), clinical validation has not been consolidated for antioxidants and mitochondrial drugs in sepsis and septic hearts. More recent findings from our group and others depicted a rather pivotal role for autophagy dysregulation in the onset and development of septic cardiomyopathy (Pang, Peng, et al, ; Pang, Zheng, et al, ; Piquereau et al, ; Ren et al, ; Sun et al, ), although the mechanism behind sepsis‐induced autophagy dysregulation is still unclear.…”

Section: Introductionmentioning

confidence: 99%

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Luo

Fan

Yang

et al. 2020

British J Pharmacology

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Background and Purpose Lipopolysaccharides (LPS), an outer membrane component of Gram‐negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF‐CD74 in septic cardiomyopathy. Experimental Approach This study evaluated the impact of CD74 ablation on endotoxaemia‐induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. Key Results Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2− production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down‐regulated Skp2, an F‐box component of Skp1/Cullin/F‐box protein‐type ubiquitin ligase, while up‐regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP‐LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS‐induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5‐AzaC ameliorated LPS‐induced GFP‐LC3B formation and cardiomyocyte contractile dysfunction. Conclusion and Implications Our data suggested that CD74 ablation protected against LPS‐induced cardiac anomalies, O2− production, inflammation and apoptosis through suppression of autophagy in a Skp2‐SUV39H1‐mediated mechanism.

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Section: Introductionmentioning

confidence: 99%

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Luo

Fan

Yang

et al. 2020

British J Pharmacology

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“…Accumulating evidence demonstrates the causative involvement of mitochondrial dysregulation [ 4 ]. Mitochondrion is a semi-self-replicating organelle containing its own genome.…”

Section: Introductionmentioning

confidence: 99%

“…Nrf2 knockdown inhibits mitochondrial biogenesis with downregulation of PGC-1α [ 11 ], while PGC-1α potentiates Nrf2-mediated antioxidant response [ 12 ], indicative of the presence of Nrf2/PGC-1α feedback loop. Mitochondrial reactive oxygen species (ROS) is a driving force for mitochondrial dysfunction in septic cardiomyopathy [ 4 ], while PGC-1α is responsive to the alternations in cellular energetic demands and redox status [ 13 ]. Therefore, finding the role of Nrf2 in the cooperation with PGC-1α would provide important insight into the action of antioxidant defenses from the aspect of mitochondrial biogenesis.…”

Section: Introductionmentioning

confidence: 99%

Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis

et al. 2021

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Septic cardiomyopathy is characterized by impaired contractive function with mitochondrial dysregulation. Songorine is a typical active C 20 -diterpene alkaloid from the lateral root of Aconitum carmichaelii , which has been used for the treatment of heart failure. This study investigated the protective role of songorine in septic heart injury from the aspect of mitochondrial biogenesis. Songorine (10, 50 mg/kg) protected cardiac contractive function against endotoxin insult in mice with Nrf2 induction. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial reactive oxygen species (ROS) production and redistributed STIM1 to interact with Orai1 for the formation of calcium release-activated calcium (CRAC) channels, mediating calcium influx, which were prevented by songorine, likely due to ROS suppression. Songorine activated Nrf2 by promoting Keap1 degradation, having a contribution to enhancing antioxidant defenses. When LPS shifted metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) in cardiomyocytes, songorine upregulated mitochondrial genes involved in fatty acid β-oxidation, tricarboxylic acid (TCA) cycle and electron transport chain in a manner dependent on Nrf2, resultantly protecting the capability of OXPHOS. Songorine increased luciferase report gene activities of nuclear respiratory factor-1 ( Nrf1 ) and mitochondrial transcription factor A ( Tfam ) dependently on Nrf2, indicative of the regulation of Nrf2/ARE and NRF1 signaling cascades. Songorine promoted PGC-1α binding to Nrf2, and the cooperation was required for songorine to activate Nrf2/ARE and NRF1 for the control of mitochondrial quality and quantity. In support, the beneficial effects of songorine on cardioprotection and mitochondrial biogenesis were diminished by cardiac Nrf2 deficiency in mice subjected to challenge. Taken together, these results showed that Nrf2 transcriptionally promoted mitochondrial biogenesis in cooperation with PGC-1α. Songorine activated Nrf2/ARE and NRF1 signaling cascades to rescue cardiomyocytes from endotoxin insult, suggesting that protection of mitochondrial biogenesis was a way for pharmacological intervention to prevent septic heart injury.

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“…It has been reported that the role of ROS is increasingly gaining attention in the chemotherapy mechanisms of tumors [49]. Studies have shown that, PTX can affect the activities of SOD and MDA in cancer cells [50], which will result in the severely imbalanced antioxidant capacity in cancer cells as well as the markedly elevated ROS level, eventually killing the cancer cells. Some recent studies have reported that various forms of Se can react with the reducing glutathione to produce ROS, which can thereby trigger some apoptotic signaling pathways and promote cancer cell apoptosis [51].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

Zhang

et al. 2019

Int. J. Biol. Sci.

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Diselenide-containing paclitaxel nanoparticles (SePTX NPs) indicated selectivity of cytotoxicity between cancerous and normal cells in our previous work. Herein, the mechanism is revealed by molecular biology in detail. Cancer cells and normal cells were treated with the SePTX NPs and cell proliferation was measured using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell morphology. Measurement of reactive oxygen species (ROS) levels and biochemical parameters were employed to monitor oxidative stress of the cells. JC-1 assay was used to detect the mitochondrial dysfunction of the cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect apoptosis of the cells. Immunofluorescence analysis and western blotting were employed to monitor changes in signaling pathway-related proteins. Compared with PTX, SePTX NPs has a good selectivity to cancer cells and can obviously induce the proliferation damage of cancer cells, but has no significant toxicity to normal cells, indicating that SePTX NPs has a specific killing effect on cancer cells. The results of mechanism research show that SePTX NPs can successfully inhibit the depolymerization of microtubules and induce cell cycle arrest, which is related to the upregulation of p53 and CyclinB1. Simultaneously, SePTX NPs can successfully induce oxidative stress, cause mitochondrial dysfunction, resulting in mitochondrial pathway-mediated apoptosis, which is related to the upregulation of autophagy-related protein LC3-II. On the other hand, lewis lung cancer C57BL/6 mice were used to evaluate the anti-tumor effects of SePTX NPs in vivo. Our data show that SePTX NPs exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects. Collectively, these data indicate that the high antitumor effect and selective cytotoxicities of SePTX NPs is promising in future cancer therapy.

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Involvement of Mitochondrial Disorders in Septic Cardiomyopathy

Cited by 61 publications

References 116 publications

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

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